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47 gesichtete, geschützte Fragmente: Plagiat

[1.] Rlm/Fragment 004 02 - Diskussion
Bearbeitet: 10. December 2014, 23:43 Singulus
Erstellt: 4. December 2014, 10:18 (SleepyHollow02)
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Androgens bind to a specific androgen receptor (AR), a ligand-dependent transcription factor which controls the expression of a large number of downstream target genes. The androgen receptor (AR) is a critical effector of prostate cancer development and progression and for this reason , [sic] AR ablation is the first line of therapeutic intervention in the treatment of disseminated prostate cancers. However, recurrent tumors arise within a median of 2-3 years wherein androgen signaling has been inappropriately restored (2).

2)Feldman BJ,Feldman D,The development of androgen-independent prostate cancer. ) Nat Rev Cancer. 2001 Oct;1(1):34-45.

The androgen receptor (AR) is a critical effector of prostate cancer development and progression.The dependence of this tumor type on AR activity is exploited in treatment of disseminated prostate cancers, wherein ablation of AR function (achieved either through ligand depletion and/or the use of AR antagonists) is the first line of therapeutic intervention.

However, recurrent tumors arise within a median of 2-3 years, wherein androgen signaling has been inappropriately restored [Feldman and Feldman, 2001].

Androgen exerts its biological effects through the androgen receptor (AR), a member of the nuclear receptor superfamily that acts as a ligand dependent transcription factor [Evans, 1988; Mangelsdorf et al., 1995; Shand and Gelmann, 2006; Trapman and Brinkmann, 1996].

Anmerkungen
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(SleepyHollow02) Singulus

[2.] Rlm/Fragment 005 05 - Diskussion
Bearbeitet: 1. December 2014, 13:39 Singulus
Erstellt: 2. November 2014, 21:40 (Graf Isolan)
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One possible mechanism by which a prostate cancer circumvents the effects of androgen ablation therapy is by increasing its sensitivity to very low levels of androgens. There are several potential mechanisms that would allow increased tumor-cell proliferation, despite low circulating androgens in the patient. One mechanism to accomplish this is by increasing the expression of the AR itself. Approximately 30% of tumors that become androgen independent after ablation therapy have amplified the AR gene (3). A second hypersensitive mechanism for tumor progression results in high-level expression of the AR, increased stability, and enhanced nuclear localization of AR in recurrent tumor cells. A third hypersensitive mechanism to circumvent androgen ablation therapy is by increasing the local production of androgens, to compensate for the overall decline in circulating testosterone. Prostate cells could increase the rate of conversion of testosterone to the more potent hormone DHT by increasing 5α-reductase activity.

3) Koivisto, P. et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 57, 314–319.

[Page 36]

Type 1: the hypersensitive pathway

One possible mechanism by which a prostate cancer circumvents the effects of androgen ablation therapy is by increasing its sensitivity to very low levels of androgens. [...]

AR amplification. There are several potential mechanisms that would allow increased tumour-cell proliferation, despite low circulating androgens in the patient. One mechanism to accomplish this is by increasing the expression of the AR itself. [...] Approximately 30% of tumours that become androgen independent after ablation therapy have amplified the AR gene, resulting in increased AR expression, whereas none of the primary tumours from the same patients before androgen ablation had an AR gene amplification15,25.

[Page 37]

Increased AR sensitivity. A second hypersensitive mechanism for tumour progression was found in animal models of the transition from androgen-dependent prostate cancer to apparent AIPC27.This pathway results in high-level expression of the AR, increased stability, and enhanced nuclear localization of AR in recurrent tumour cells. [...]

Increased androgen levels. A third hypersensitive mechanism to circumvent androgen ablation therapy is by increasing the local production of androgens, to compensate for the overall decline in circulating testosterone. Prostate cells could increase the rate of conversion of testosterone to the more potent hormone DHT by increasing 5α-reductase activity.


15. Koivisto, P. et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 57, 314–319.

25. Visakorpi, T. et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nature Genet. 9, 401–406 (1995). This study defined the amplified AR as a mechanism for the hypersensitive pathway.

27. Gregory, C. W., Johnson, R. T. Jr, Mohler, J. L., French, F. S. & Wilson, E. M. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 61, 2892–2898.

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(Graf Isolan), SleepyHollow02

[3.] Rlm/Fragment 006 02 - Diskussion
Bearbeitet: 8. February 2015, 20:28 Schumann
Erstellt: 29. November 2014, 20:26 (SleepyHollow02)
Feldman and Feldman 2001, Fragment, Gesichtet, Rlm, SMWFragment, Schutzlevel sysop, Verschleierung

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Some of these tumors, at least initially, have adapted to the low androgen environment, others acquire mutations that allow them to circumvent the normal growth regulation by androgens. It seems that many cases of AIPC do not develop from a loss of androgen signaling, but rather from the acquisition of genetic changes that lead to aberrant activation of the androgen-signaling axis. These changes are usually missense mutations in the AR gene that decrease the specificity of ligand binding and allow inappropriate activation by various non-androgen steroids and androgen antagonists (4) . In other cases some growth factors such as insulin-like growth-factor- 1 (IGF- 1), keratinocyte growth factor (KGF) and epidermal growth factor (EGF), can activate the AR, creating an outlaw receptor, and can therefore induce AR target genes in the absence of androgen (5). These are just some of the mechanisms in which cells can use to escape androgen ablation and it is also possible that a single cancer uses several mechanisms either initially or in a multistep progression to AIPC.

4) Buchanan, G. et al. Collocation of androgen receptor gene mutations in prostate cancer. Clin. Cancer Res. 7, 1273–1281 (2001).

5) Culig, Z. et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 54, 5474–5478 (1994)

Whereas some of these tumours, at least initially, have adapted to the low-androgen environment, others acquire mutations that allow them to circumvent the normal growth regulation by androgens. It seems that many cases of AIPC do not develop from a loss of androgen signalling, but rather from the acquisition of genetic changes that lead to aberrant activation of the androgen signalling axis21. These changes are usually missense mutations in the AR gene that decrease the specificity of ligand binding and allow inappropriate activation by various non-androgen steroids and androgen antagonists.

[page 41:]

Certain growth factors, such as insulin-like growth-factor-1 (IGF- 1), keratinocyte growth factor (KGF) and epidermal growth factor (EGF), can activate the AR, creating an outlaw receptor, and can therefore induce AR target genes in the absence of androgen59. [...] It is also possible, if not likely, that a single cancer uses several mechanisms either initially or in a multistep progression to AIPC


59. Culig, Z. et al. Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res. 54, 5474–5478 (1994). Early description of growth-factor activation of AR in the absence of ligand, developing the basis for the outlaw AR pathway.

Anmerkungen
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(SleepyHollow02) Singulus

[4.] Rlm/Fragment 006 18 - Diskussion
Bearbeitet: 10. December 2014, 23:19 Hindemith
Erstellt: 30. November 2014, 17:02 (SleepyHollow02)
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The appropriate regulation of androgen activity is necessary for a range of developmental and physiological processes, particularly male sexual development and maturation. The appropriate regulation of androgen activity is necessary for a range of developmental and physiological processes, particularly male sexual development and maturation.
Anmerkungen

The source is not mentioned. To be continued on the following page.

Sichter
(SleepyHollow02), Hindemith

[5.] Rlm/Fragment 007 01 - Diskussion
Bearbeitet: 1. December 2014, 13:42 Singulus
Erstellt: 2. November 2014, 22:12 (Graf Isolan)
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However, excessive production of adrenal androgens can cause premature puberty in young boys and their hypersecretion in females produce a masculine pattern of body hair and cessation of menstruation(6). Their miss-regulation [sic] is also implicated in the formation and progression of prostatic adenocarcinoma (7). Therefore, the removal of testicular androgens by castration has long been recognized to result in tumor regression, and surgical or pharmacological androgen ablation remains the predominant form of treatment for advanced prostate cancer. Androgen ablation therapy is often combined with the treatment of nonsteroidal antiandrogens, such as hydroxyflutamide, to block residual androgens action. Androgen Replacement Therapy has been in use for over 60 years to treat, with proven efficacy and safety, on patients with male hypogonadal disorders and/or failure of sexual development. Apart from that, the last decade has witnessed a wider therapeutic role of androgens for nonclassical indications.

6) Culig Z, Bartsch G 2006 Androgen axis in prostate cancer. J Cell Biochem 99:373–381

7) Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ 2003 Constitutive activation of the ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981–1989

16) Culig Z, Klocker H, Bartsch G, Steiner H, HobischA [sic] Anrogen [sic] Receptor in Prostate Cancer J Urol. 2003 Oct;170(4): 1363-1369.

17) Petre CE, Wetherill YB, Danielsen M, Knudsen KE. Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem 2002 Jan 18;277 (3):2207-15. Epub 2001 Nov 19.

However, excessive production of adrenal androgens can cause premature puberty in young boys and their hypersecretion in females, may produce a masculine pattern of body hair and cessation of menstruation (Ref.4). Their mis-regulation is also implicated in the formation and progression of prostatic adenocarcinoma (Ref.3). Therefore, the removal of testicular androgens by castration has long been recognized to result in tumor regression, and surgical or pharmacological androgen ablation remain the predominant form of treatment for advanced prostate cancer. Androgen ablation therapy is often combined with treatment with nonsteroidal antiandrogens, such as hydroxyflutamide, to block residual adrenal androgen action. Androgen Replacement Therapy has been in use for over 60 years to treat, with proven efficacy and safety, on patients with male hypogonadal disorders and/or failure of sexual development. Apart from that, the last decade has witnessed a wider therapeutic role of androgens for nonclassical indications.

3. Culig Z, Klocker H, Bartsch G, Steiner H, Hobisch A
Androgen Receptors in Prostate Cancer.
J Urol. 2003 Oct;170(4):1363-1369.

4. Petre CE, Wetherill YB, Danielsen M, Knudsen KE
Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity
J Biol Chem. 2002 Jan 18;277(3):2207-15. Epub 2001 Nov 19.

Anmerkungen

Not marked as a citation.

There is no reference (16) in the main text of Rlm's thesis.

Mark the difference in the placement of the year in the references (twice right behind the names, twice after the name of the journal) in Rlm demonstrated here, which is an indication of two different sources for these references. Furthermore it should be noted that this corresponds to the particular number of the journal being listed as well (in contrast to just the volume being identified).

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(Graf Isolan), SleepyHollow02

[6.] Rlm/Fragment 009 01 - Diskussion
Bearbeitet: 1. December 2014, 17:33 Singulus
Erstellt: 30. November 2014, 18:06 (Graf Isolan)
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The C-terminal region of the AR, the hinge region and ligand-binding domain (LBD) is responsible for ligand binding and receptor dimerization. The well conserved DNA binding domain consists of 68 amino acids with two zinc finger structures. In contrast to several other hormone-regulated nuclear receptors, the AR lacks an intrinsic activation function 2 in the LBD domain. The LBD domain, which consists of twelve α-helices, projects away from the hormone-binding pocket in the absence of ligand and undergoes substantial conformational changes in the presence of ligand . [sic] The folding of the most C-terminal helix 12 (H12) over the ligand-binding pocket in turn creates new structural surfaces that bind coactivators required for efficient trans-activation. The C-terminal region of the AR, including the hinge region and ligand-binding domain (LBD) is responsible for ligand binding and dimerization. The well conserved DNA binding domain consists of 68 amino acids with two zinc finger structures. The N-terminal region contributes to transcriptional activation through its activation function 1 (2). In contrast to several other hormone-regulated nuclear receptors, the AR lacks an intrinsic activation function 2 function in the LBD. The LBD, which consists of twelve α-helices, projects away from the hormone-binding pocket in the absence of ligand and undergoes substantial conformational changes in the presence of ligand (3). The folding of the most C-terminal helix 12 (H12) over the ligand-binding pocket in turn creates new structural surfaces that bind coactivators required for efficient trans-activation.

2. Alen, P., Claessens, F., Verhoeven, G., Rombauts, W., and Peeters, B. (1999) Mol. Cell. Biol. 19, 6085–6097

3. Marhefka, C. A., Moore, B. M., 2nd, Bishop, T. C., Kirkovsky, L., Mukherjee, A., Dalton, J. T., and Miller, D. D. (2001) J. Med. Chem. 44, 1729–1740

Anmerkungen

Not marked as a citation.

Mark the superfluous blank space where formerly a reference number was given.

Sichter
(Graf Isolan), SleepyHollow02

[7.] Rlm/Fragment 010 04 - Diskussion
Bearbeitet: 10. December 2014, 23:37 Singulus
Erstellt: 29. November 2014, 20:43 (SleepyHollow02)
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Testosterone — the main circulating androgen — is secreted primarily by the testes, but is also formed by peripheral conversion of adrenal steroids. It circulates in the blood, where it is bound to albumin and sex-hormone-binding globulin (SHBG), with a small fraction dissolved freely in the serum. When free testosterone enters into prostate cells , it is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (SRD5A2). DHT is the more active hormone, having fivefold higher affinity for the androgen receptor (AR) than does testosterone(11).

11) Nash AF , Melezinek I. The role of prostate specific antigen measurement in the detection and management of prostate cancer. Endocr Relat Cancer. 2000 Mar;7(1):37-51.

Testosterone — the main circulating androgen — is secreted primarily by the testes, but is also formed by peripheral conversion of adrenal steroids4. It circulates in the blood, where it is bound to albumin and sex-hormone-binding globulin (SHBG), with a small fraction dissolved freely in the serum. When free testosterone enters prostate cells (BOX 2), 90% is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase (SRD5A2). DHT is the more active hormone, having fivefold higher affinity for the androgen receptor (AR) than does testosterone.

4. Griffin, J. E. & Wilson, J. D. in Williams Testbook of Endocrinology 9th edn (eds Wilson, J. D., Foster, D. W., Kronenberg, H. M. & Larsen, P. R.) 819–876 (W. B. Saunders & Co., Philadelphia, 1998).

Anmerkungen
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(SleepyHollow02) Singulus

[8.] Rlm/Fragment 010 13 - Diskussion
Bearbeitet: 1. December 2014, 14:06 Singulus
Erstellt: 30. November 2014, 21:28 (Graf Isolan)
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While the subsets of AR target genes that underlie each cellular outcome have yet to be clearly defined, discovery of at least one major AR-dependent target gene, prostate specific antigen (PSA) has had a major impact on disease management (12).

10) Riegman PH, Vlietstra RJ, van der Korput JA, Brinkmann AO, Trapman J The promoter of the prostate-specific antigen gene contains a functional androgen responsive element. Mol Endocrinol.1991 Dec;5(12):1921-30.

12) Ryan CJ, Smith A, Lal P, Satagopan J, Reuter V, Scardino P, Gerald W, Scher HI. Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression Urology. 2006 Oct;68(4):834-9

While the subsets of AR target genes that underlie each cellular outcome have yet to be clearly defined, discovery of at least one major AR-dependent target gene, prostate specific antigen (PSA) [Riegman et al., 1991], has had a major impact on disease management.

Riegman, P. H., Vlietstra, R. J., van der Korput, J. A., Brinkmann, A. O. and Trapman, J. (1991) The promoter of the prostate-specific antigen gene contains a functional androgen responsive element Mol Endocrinol 5, 1921-30.

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Sichter
(Graf Isolan), SleepyHollow02

[9.] Rlm/Fragment 011 03 - Diskussion
Bearbeitet: 1. December 2014, 14:07 Singulus
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Specifically, serum PSA is monitored clinically to detect early stage disease, track tumor burden, monitor the efficacy of therapeutic intervention, and detect the emergence of recurrent tumors post-therapy (13,14).

11) Nash AF , Melezinek I. The role of prostate specific antigen measurement in the detection and management of prostate cancer. Endocr Relat Cancer. 2000 Mar;7(1):37-51.

12) Ryan CJ, Smith A, Lal P, Satagopan J, Reuter V, Scardino P, Gerald W, Scher HI. Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression Urology. 2006 Oct;68(4):834-9

13) Reigman PJH, Vliestra RJ, van der Korput JAGM, Romijn JC, Trapman J Characterization of the prostate specific antigen gene: a novel kallikrein-like gene. Biochem Biophys Res Commun 159:95–102

14) Lilja H A kallikrein-like serine protease in prostatic fluid cleaves the predominant seminal vesicle protein. J Clin Invest 76: 1899–1903

Specifically, serum PSA is monitored clinically to detect early stage disease, track tumor burden, monitor the efficacy of therapeutic intervention, and detect the emergence of recurrent tumors post-therapy [Nash and Melezinek, 2000; Ryan et al., 2006].

Nash, A. F. and Melezinek, I. (2000) The role of prostate specific antigen measurement in the detection and management of prostate cancer Endocr Relat Cancer 7, 37-51.

Ryan, C. J., Smith, A., Lal, P., Satagopan, J., Reuter, V., Scardino, P., Gerald, W. and Scher, H. I. (2006) Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression Urology 68, 834-9.

Anmerkungen

Nothing has been marked as a citation.

In the original article, this passage follows immediately after the one documented in Rlm/Fragment_010_13.

Sichter
(Graf Isolan), SleepyHollow02

[10.] Rlm/Fragment 011 10 - Diskussion
Bearbeitet: 10. December 2014, 23:21 Hindemith
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The binding of androgens to AR induces dissociation of the AR from the HSPs proteins (Heat-Shock-Proteins) and subsequent receptor dimerization and translocation into the nucleus , facilitating the ability of AR to bind its cognate response elements, and recruit coregulators to promote the expression of target genes. The transcriptional activity of AR is greatly modulated by coregulatory proteins. Coactivators such as ARA70 ( Androgen Coactivators 70Kd) and ARA55 stabilize the process of ligand binding to AR. The ability of AR to be translocated into the nucleus is regulated by several coregulators such as the F-Actin binding protein Filamin. The binding of androgens to AR induces dissociation of the AR from the HSPs and subsequent receptor dimerization and translocation into the nucleus, facilitating the ability of AR to bind to its cognate response element, and recruit coregulators to promote the expression of target genes. The transcriptional activity of AR is greatly modulated by coregulatory proteins. Coactivators such as ARA70 (Androgen Receptor Coactivator, 70-Kd) and ARA55 stabilize the process of ligand binding to AR. The ability of AR to be translocated to the nucleus is regulated by several coregulators, for example, the F-Actin binding protein: Filamin.
Anmerkungen

The source is not given.

Sichter
(SleepyHollow02), Hindemith

[11.] Rlm/Fragment 012 01 - Diskussion
Bearbeitet: 10. December 2014, 23:26 Hindemith
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Inside the nucleus AR interacts with DNA by targeting specific nucleotide palindromic sequences termed Androgen Response Element (17). A number of coregulators themselves perform enzymatic activities such as phosphorylation or acetylation, modifying either the chromatin surrounding the promoter of the target gene or other coregulators. Among coactivators, the acetyltranferase , CBP (CREB Binding Protein) , the closely related p300 and other nuclear receptor coactivators p/CAF(p300/CBP Associated Factor), SRC1( Steroid Receptor Coactivator-1), and SRC3 (18).

17) Petre CE, Wetherill YB, Danielsen M, Knudsen KE. Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem 2002 Jan 18;277 (3):2207-15. Epub 2001 Nov 19.

18) Hao Yun Wong, Jan A. Burghoorn, Marije van Leeuwen, Petra E. De Ruiter, Esther Schippers, Leen J. Blok, Ka Wan LI, Henk L. Dekker, Luitzen De Jong, Jan Trapman, J. Anton Grotegoedand Albert O. Btinkmann. Phosphorylation of androgen receptor isoforms.Biochem J. 2004 Oct 15;383(Pt 2):267-76

Inside the nucleus, AR interacts with DNA by targeting specific nucleotide palindromic sequences termed ARE (Androgen Response Element) (Ref.2).

A number of coregulators themselves perform enzymatic activities such as phosphorylation or acetylation, modifying either the chromatin surrounding the promoter of the target gene or other coregulators. The prototypic coactivators of this type that possess acetyltransferase activity include, CBP (CREB Binding Protein), the closely related p300 and other nuclear receptor coactivators: p/CAF (p300/CBP Associated Factor), SRC1 (Steroid Receptor Coactivator-1), and SRC3 (Ref.3).


2. Lee DK, Chang C Molecular communication between androgen receptor and general transcription machinery. J Steroid Biochem Mol Biol. 2003 Jan;84(1):41-9.

3. Culig Z, Klocker H, Bartsch G, Steiner H, Hobisch A Androgen Receptors in Prostate Cancer. J Urol. 2003 Oct;170(4):1363-1369.

Anmerkungen

The source is not given.

Note that Petre et al. (2002) is the reference 4 in the source:

4. Petre CE, Wetherill YB, Danielsen M, Knudsen KE Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem. 2002 Jan 18;277(3):2207-15. Epub 2001 Nov 19.

Sichter
(SleepyHollow02), Hindemith

[12.] Rlm/Fragment 013 01 - Diskussion
Bearbeitet: 10. December 2014, 23:28 Singulus
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Fig2. Androgen action. Testosterone circulates in the blood bound to albumin (not shown) and sex-hormone-binding globulin (SHBG), and exchanges with free testosterone. Free testosterone enters prostate cells and is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Binding of DHT to the androgen receptor (AR) induces dissociation from heat-shock proteins (HSPs) and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes. Co-activators (such as ARA70) and corepressors (not shown) also bind the AR complex, facilitating or preventing, respectively, its interaction with the general transcription apparatus (GTA). Activation (or repression) of target genes leads to biological responses including growth, survival and the production of prostate-specific antigen (PSA). Figure 1 Androgen action. Testosterone circulates in the blood bound to albumin (not shown) and sex-hormone-binding globulin (SHBG), and exchanges with free testosterone. Free testosterone enters prostate cells and is converted to dihydrotestosterone (DHT) by the enzyme 5α-reductase. Binding of DHT to the androgen receptor (AR) induces dissociation from heat-shock proteins (HSPs) and receptor phosphorylation. The AR dimerizes and can bind to androgen-response elements in the promoter regions of target genes6. Co-activators (such as ARA70) and corepressors (not shown) also bind the AR complex, facilitating or preventing, respectively, its interaction with the general transcription apparatus (GTA). Activation (or repression) of target genes leads to biological responses including growth, survival and the production of prostate-specific antigen (PSA).

6. Brinkmann, A. O. et al. Mechanisms of androgen receptor activation and function. J. Steroid Biochem. Mol. Biol. 69, 307–313 (1999).

Anmerkungen
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(SleepyHollow02) Singulus

[13.] Rlm/Fragment 014 01 - Diskussion
Bearbeitet: 10. December 2014, 23:33 Hindemith
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PIAS (Protein Inhibitor of Activated Signal Transducer and Activator of Transcription STAT) family of proteins and ANPK ( Androgen Receptor-Interacting Nuclear Kinase) play major function. Transcriptional activation by AR ultimately requires the recruitment of RNA Pol II( RNA polymerase II) to the promoter of target genes. RNA Pol II recruitment is mediated through the assembly of GTFs (General Transcription Factor)to form the pre-initiation complex, the first step of which is the binding of TBP (TATA box-Binding Protein)near the transcriptional start site . TBP is part of multiprotein complex, the first step of which is the binding of TBP near the transcriptional start site. TBP is part of multiprotein complex which includes TFIID (Transcriptional Factor –IID) that induces DNA bending , bringing sequences upstream of the TATA element in closer proximity, and presumably enabling interaction between GTFs and steroid receptor-coregulators complexes. TFIIB binds directly to TBP and recruits the TFIIF-RNA Pol II complex. TFIIF interacts with TFIIB and RNA Pol II and has a role in transcription initiation and elongation. PIAS [Protein Inhibitor of Activated Signal Transducer and Activator of Transcription (STAT)] family of proteins and ANPK (Androgen Receptor-Interacting Nuclear Kinase) also interact with and coactivate AR. Transcriptional activation by AR ultimately requires the recruitment of RNA Pol II (RNA polymerase-II) to the promoter of target genes. RNA Pol II recruitment is mediated through the assembly of GTFs (General Transcription Factors) to form the preinitiation complex, the first step of which is the binding of TBP (TATA box-Binding Protein) near the transcriptional start site. TBP is part of a multiprotein complex, TFIID (Transcription Factor-IID), which also contains general and promoter-specific TAFII (TBP-Associated Factors) proteins. TBP binding induces DNA bending, bringing sequences upstream of the TATA element in closer proximity, presumably enabling interaction between GTFs and steroid receptor-coregulator complexes. TFIIB binds directly to TBP and functions to recruit the TFIIF-RNA Pol II complex. TFIIF domains, in addition to interacting with TFIIB and RNA Pol II, apparently also serve in transcription initiation and elongation.
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[14.] Rlm/Fragment 015 01 - Diskussion
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The ATPase/ Kinase TFIIE and helicase TFIIH are than recruited to RNA Pol II to facilitate DNA strand separation before transcription initiation. TFIIE and TFIIF are acetylated by p300 and p/CAF. Ubiquitin ligase activity has been identified for two AR coactivators, ARA54 and E6-AP.The coactivators with ubiquitin ligase activity contribute to nuclear receptor transactivation through targeting the degradation of corepressor. AR can also interact with a number of transcription factor including Activator Protein-1,SMAD3( Sma and Mad Related Family),NF-KappaB (Nuclear Factor-KappaB), SRY (Sex-determining Region-Y), and the Ets family of transcription factors.

Transcriptional corepression of androgen-bound AR can be attributed to three corepressors: cyclin D1, calreticulin and HBO1.Cyclin-D1 inhibits AR transactivation through a mechanism independent of its function in cell cycle regulation (7).

The calcium –binding protein calreticulinis [sic] localized to the endoplasmic reticulum and in the nucleus and has also been characterized as corepressor of AR.


7) Bakin RE, Gioeli D, Sikes RA, Bissonette EA, Weber MJ 2003 Constitutive activation of the ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res 63:1981–1989

The ATPase and kinase TFIIE and the helicase TFIIH are then recruited to RNA Pol II to facilitate DNA strand separation before transcription initiation. TFIIE and TFIIF recruitment to RNA pol II are acetylated by p300 and p/CAF (Ref.2). Ubiquitin ligase activity has been identified for two AR coactivators, ARA54 and E6-AP. The coactivators with ubiquitin ligase activity contribute to nuclear receptor transcription through targeting the degradation of corepressors. AR can also interact with a number of transcription factors including Activator Protein-1, SMAD3 (Sma and Mad Related Family), NF-KappaB (Nuclear Factor-KappaB), SRY (Sex-determining Region-Y), and the Ets family of transcription factors.

Transcriptional corepression of androgen-bound AR can be attributed to three corepressors: cyclin-D1, calreticulin and HBO1. Cyclin-D1 inhibits AR transactivation through a mechanism independent of its function in cell cycle regulation (Ref.4). The calcium-binding protein calreticulin is localized to the endoplasmic reticulum and nucleus and has also been characterized as a corepressor of AR.


2. Lee DK, Chang C Molecular communication between androgen receptor and general transcription machinery. J Steroid Biochem Mol Biol. 2003 Jan;84(1):41-9.

4. Petre CE, Wetherill YB, Danielsen M, Knudsen KE Cyclin D1: mechanism and consequence of androgen receptor co-repressor activity. J Biol Chem. 2002 Jan 18;277(3):2207-15. Epub 2001 Nov 19.

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[15.] Rlm/Fragment 016 01 - Diskussion
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The AR corepressor HBO1 is a member of MYST protein family that is characterized by a homologous zinc finger and carries an acetyltransferase domain. Although AR is normally thought to function as a homodimer, it has been found to heterodimerize with other nuclear receptors including the ER( Estrogen Receptor), GR ( Glucocorticoid Receptor) and TR4(Testicular Orphan Receptor 4) and in each case result in a decrease in AR transcriptional activity. In addition to the transcriptional or genomic mode of action by steroids, androgens, can also exert rapid, nongenomic effect. Nongenomic steroid activity typically involves the rapid induction of conventional second messenger signal transduction cascades. Nongenomic action of androgens can occur through multiple receptors. Androgens also stimulate an elevation in intracellular Ca2+ through GPCR(G-Protein Coupled Receptor) by activating an influx through nonvoltage-gated Ca2+ channels.The elevation of intracellular calcium activates signal transduction cascades, including PKA(Protein Kinase-A),PKC(Protein Kinase-C), and MAPKs( Mitogen Activated Protein Kinase), that can modulate the activity of the ARs and other transcription factors.

AR also interacts with intracellular tyrosine Kinase c-Src, triggering c-Src activation. One of the targets of c-Src is the adapter protein SHR [(SH2 Containing Protein), an upstream regulator of the MAPK pathway (18).]


18) Hao Yun Wong, Jan A. Burghoorn, Marije van Leeuwen, Petra E. De Ruiter, Esther Schippers, Leen J. Blok, Ka Wan LI, Henk L. Dekker, Luitzen De Jong, Jan Trapman, J. Anton Grotegoedand Albert O. Btinkmann. Phosphorylation of androgen receptor isoforms.Biochem J. 2004 Oct 15;383(Pt 2):267-76

The AR corepressor HBO1 is a member of the MYST protein family that is characterized by a homologous zinc finger and carries an acetyltransferase domain. Although AR is normally thought to function as a homodimer, it has been found to heterodimerize with other nuclear receptors including the ER (Estrogen Receptor), GR (Glucocorticoid Receptor) and TR4 (Testicular Orphan Receptor-4) and in each case result in a decrease in AR transcriptional activity.

In addition to the transcriptional or genomic mode of action by steroids, androgens, can also exert rapid, nongenomic effects. Nongenomic steroid activity typically involves the rapid induction of conventional second messenger signal transduction cascades. Nongenomic action of androgens can occur through multiple receptors. [...] Androgens also stimulate an elevation in intracellular Ca2+ through a GPCR (G-Protein Coupled Receptor) by activating an influx through nonvoltage-gated Ca2+ channels. The elevation of intracellular calcium activates signal transduction cascades, including PKA (Protein Kinase-A), PKC (Protein Kinase-C), and MAPKs (Mitogen-Activated Protein Kinase), that can modulate the activity of the ARs and other transcription factors. AR also interacts with the intracellular tyrosine kinase c-Src, triggering c-Src activation. One of the targets of c-Src is the adapter protein SHC (SH2 Containing Protein), an upstream regulator of the MAPK pathway.

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[16.] Rlm/Fragment 017 01 - Diskussion
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[One of the targets of c-Src is the adapter protein SHR] (SH2 Containing Protein), an upstream regulator of the MAPK pathway (18). AR phosphorylation by ERK2 is associated with enhanced AR transcriptional activity and an increased ability to recruit the coactivator ARA 70.The SRC family of transcriptional coactivators: SRC1, SRC3, and TIF2( Transcription Intermedary Factor -2) are targets of MAPK phosphoryation that result s in an increased ability of these coactivators to recruit additional coactivators complexes to the DNA-bound receptor. The non genomic rapid stimulation of the second messenger cascades by androgens may ultimately exert biological effects through modulation of the transcriptional activity of AR or other transcription factors. Such modulation may occur through direct phosphorylation of activators or their coregulators.

18) Hao Yun Wong, Jan A. Burghoorn, Marije van Leeuwen, Petra E. De Ruiter, Esther Schippers, Leen J. Blok, Ka Wan LI, Henk L. Dekker, Luitzen De Jong, Jan Trapman, J. Anton Grotegoedand Albert O. Btinkmann. Phosphorylation of androgen receptor isoforms.Biochem J. 2004 Oct 15;383(Pt 2):267-76

One of the targets of c-Src is the adapter protein SHC (SH2 Containing Protein), an upstream regulator of the MAPK pathway. [...] AR phosphorylation by ERK2 is associated with enhanced AR transcriptional activity and an increased ability to recruit the coactivator ARA70. The SRC family of transcriptional coactivators: SRC1, SRC3, and TIF2 (Transcription Intermediary Factor-2) are targets of MAPK phosphorylation that results in an increased ability of these coactivators to recruit additional coactivator complexes to the DNA-bound receptor. The nongenomic, rapid stimulation of second messenger cascades by androgens may ultimately exert biological effects through modulation of the transcriptional activity of AR or other transcription factors. Such modulation may occur through direct phosphorylation of transcriptional activators or their coregulators (Ref.1).

1. Heinlein CA, Chang C The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol Endocrinol. 2002 Oct;16(10):2181-7.

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Post-translational modifications such as acetylation and sumoylation have been shown to influence the transactivation potential of the AR (19,20). However, it is not clear whether phosphorylation has an effect on the properties and activity of the AR. It has been shown that the AR is a phosphoprotein (21,22) and extra phosphorylation of the AR is induced when cells are exposed to androgens, in addition to the so-called basal AR phosphorylation observed in the absence of androgens(23). Phosphorylation occurs predominantly at serine residues, which are mainly located in the N-terminal domain.

[...] (24,25).


19) Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y. G., Chang, C., Hopp, T., Fuqua, S. A., Jaffray, E. et al. (2002) Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol. Cell. Biol. 22, 3373–3388

20) Poukka, H., Karvonen, U., Janne, O. A. and Palvimo, J. J. (2000) Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc. Natl. Acad. Sci. U.S.A. 97, 14145–14150

21) van Laar, J. H., Bolt-de Vries, J., Zegers, N. D., Trapman, J. and Brinkmann, A. O. (1990) Androgen receptor heterogeneity and phosphorylation in human LNCaP cells. Biochem. Biophys. Res. Commun. 166, 193–200

22) van Laar, J. H., Berrevoets, C. A., Trapman, J., Zegers, N. D. and Brinkmann, A. O. (1991) Hormone-dependent androgen receptor phosphorylation is accompanied by receptor transformation in human lymph node carcinoma of the prostate cells. J. Biol. Chem. 266, 3734–3738

23) Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J. et al. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277, 29304–29314.

24) Kuiper, G. G. and Brinkmann, A. O. (1995) Phosphotryptic peptide analysis of the human androgen receptor: detection of a hormone-induced phosphopeptide. Biochemistry 34, 1851–1857

25) Kuiper, G. G., de Ruiter, P. E., Trapman, J., Boersma, W. J., Grootegoed, J. A. and Brinkmann, A. O. (1993) Localization and hormonal stimulation of phosphorylation sites in the LNCaP-cell androgen receptor. Biochem. J. 291, 95–101

Post-translational modifications such as acetylation and sumoylation have been shown to influence the transactivation potential of the AR [12,13]. However, it is not clear whether phosphorylation has an effect on the properties and activity of the AR. It has been shown that the AR is a phosphoprotein [14,15] and extra phosphorylation of the AR is induced when cells are exposed to androgens, in addition to the so-called basal AR phosphorylation observed in the absence of androgens [15,16]. Phosphorylation occurs predominantly at serine residues [16,17], which are mainly located in the N-terminal domain [18].

12 Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y. G., Chang, C., Hopp, T., Fuqua, S. A., Jaffray, E. et al. (2002) Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Mol. Cell. Biol. 22, 3373–3388

13 Poukka, H., Karvonen, U., Janne, O. A. and Palvimo, J. J. (2000) Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1). Proc. Natl. Acad. Sci. U.S.A. 97, 14145–14150

14 van Laar, J. H., Bolt-de Vries, J., Zegers, N. D., Trapman, J. and Brinkmann, A. O. (1990) Androgen receptor heterogeneity and phosphorylation in human LNCaP cells. Biochem. Biophys. Res. Commun. 166, 193–200

15 van Laar, J. H., Berrevoets, C. A., Trapman, J., Zegers, N. D. and Brinkmann, A. O. (1991) Hormone-dependent androgen receptor phosphorylation is accompanied by receptor transformation in human lymph node carcinoma of the prostate cells. J. Biol. Chem. 266, 3734–3738

16 Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J. et al. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277, 29304–29314

17 Kuiper, G. G. and Brinkmann, A. O. (1995) Phosphotryptic peptide analysis of the human androgen receptor: detection of a hormone-induced phosphopeptide. Biochemistry 34, 1851–1857

18 Kuiper, G. G., de Ruiter, P. E., Trapman, J., Boersma, W. J., Grootegoed, J. A. and Brinkmann, A. O. (1993) Localization and hormonal stimulation of phosphorylation sites in the LNCaP-cell androgen receptor. Biochem. J. 291, 95–101

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[18.] Rlm/Fragment 019 01 - Diskussion
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Furthermore, phosphorylation is correlated with the three AR isoforms that appear on an SDS/polyacrylamide gel (26).

Within minutes after the start of de novo synthesis, the AR appears as a 110 kDa isoform, whereas the generation of the second (112 kDa) isoform appear within 15 min as shown by radioactive methioninelabelling studies. Only after hormone binding does the third (114 kDa) isoform appear. The AR isoform pattern is correlated with AR phosphorylation as was shown in previous studies by using phosphatases. The dephosphorylation of AR by phosphatases resulted in the loss of one isoform either in the presence or absence of hormone . This effect was also observed when AR phosphosites were mutated . Furthermore, several phosphorylation sites have been identified. The first identified phosphosites, Ser-81, Ser-94 and Ser-650, were found by mutagenesis analyses in combination with SDS/PAGE (27). Ser-308 was the first phosphosite identified by mutagenesis and MS Ser-16, Ser-81, Ser-94, Ser-256, Ser-308, Ser- 424 and Ser-650 were all identified and confirmed as phosphosites by mutagenesis, peptide mapping and MS (28).


26) Jenster, G., de Ruiter, P. E., van der Korput, H. A., Kuiper, G. G., Trapman, J. and Brinkmann, A. O. (1994) Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites. Biochemistry 33, 14064–14072.

27) ). [sic] Zhou, Z. X., Kemppainen, J. A. and Wilson, E. M. (1995) Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol. Endocrinol. 9, 605–615

28) Zhu, Z., Becklin, R. R., Desiderio, D. M. and Dalton, J. T. (2001) Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochem. Biophys. Res. Commun. 284, 836–844.

38) Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J., Hunt, D. F., and Weber, M. J. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277, 29304–29314.].

[Page 267]

Furthermore, phosphorylation is correlated with the three AR isoforms that appear on an SDS/polyacrylamide gel [19]. Within minutes after the start of de novo synthesis, the AR appears as a 110 kDa isoform, whereas generation of the second (112 kDa) isoform follows within 15 min as shown by radioactive methioninelabelling studies [20,21]. Only after hormone binding does the third (114 kDa) isoform appear [19]. The AR isoform pattern is correlated with AR phosphorylation as was shown in previous studies by using phosphatases. The dephosphorylation of AR by phosphatases resulted in the loss of one isoform either in the presence or absence of hormone [19]. This effect was also observed when AR phosphosites were mutated [19]. Furthermore, several phosphorylation sites have been identified. The first identified phosphosites, Ser-81, Ser-94 and Ser-650, were found by mutagenesis analyses in combination with SDS/PAGE [19,22]. Ser-308 was the first phosphosite identified by mutagenesis and MS [23]. Ser-16, Ser-81, Ser-94, Ser-256, Ser-308, Ser-424

[Page 268]

and Ser-650 were all identified and confirmed as phosphosites by mutagenesis, peptide mapping and MS [16].


16 Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J. et al. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277, 29304–29314

19 Jenster, G., de Ruiter, P. E., van der Korput, H. A., Kuiper, G. G., Trapman, J. and Brinkmann, A. O. (1994) Changes in the abundance of androgen receptor isotypes: effects of ligand treatment, glutamine-stretch variation, and mutation of putative phosphorylation sites. Biochemistry 33, 14064–14072

20 Kuiper, G. G., de Ruiter, P. E., Grootegoed, J. A. and Brinkmann, A. O. (1991) Synthesis and post-translational modification of the androgen receptor in LNCaP cells. Mol. Cell. Endocrinol. 80, 65–73

21 Kuiper, G. G., de Ruiter, P. E. and Brinkmann, A. O. (1992) Androgen receptor heterogeneity in LNCaP cells is caused by a hormone independent phosphorylation step. J. Steroid Biochem. Mol. Biol. 41, 697–700

22 Zhou, Z. X., Kemppainen, J. A. and Wilson, E. M. (1995) Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol. Endocrinol. 9, 605–615

23 Zhu, Z., Becklin, R. R., Desiderio, D. M. and Dalton, J. T. (2001) Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochem. Biophys. Res. Commun. 284, 836–844

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[19.] Rlm/Fragment 020 06 - Diskussion
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Recently Narayanan et al. discovered a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression. Here, we report the discovery of a selective nuclear androgen receptor exporter (SNARE) that functions to exclude AR from the nucleus. SNARE-1 binds wild-type and mutant ARs and efficiently inhibits their transactivation activity and ability to induce PSA gene expression.
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SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser650 of the AR facilitating the nuclear export of AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells (30).

30) Ramesh Narayanan, Muralimohan Yepuru, Adam T. Szafran, Maria Szwarc, Casey E. Bohl, Natalie L. Young, Duane D. Miller, Michael A. Mancini, and James T. Dalton. Selective Nuclear Androgen Receptor Exporter for the Treatment of Prostate Cancer. Cancer Research 2010 Jan 15;70(2):842-51. Epub 2010 Jan 12.

SNARE-1 inhibits the androgen-sensitive growth of LNCaP cells and tumor xenografts. Quantitative subcellular localization studies suggest that SNARE-1 inhibits nuclear translocation of AR, but also facilitates export of nuclear AR that has been translocated by an agonist. Mechanistic studies indicate that SNARE-1 rapidly phosphorylates p38 mitogen-activated protein kinase (MAPK) and Ser650 of the AR. Additionally, SNARE-1 was found to promote ubiquitination of AR in LNCaP cells.
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[21.] Rlm/Fragment 021 09 - Diskussion
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Transitions into and within the mitotic cell cycle are dictated by the coordinate activation of cyclin-dependent kinase (CDK)/cyclin complexes, wherein cyclin binding induces the catalytic activity of the kinase (31,32). Mitogenic signaling pathways generally induce cell cycle progression through ordered activation of CDK-cyclin complexes, whereas anti-mitogenic signals that result from extracellular events (e.g., nutrient depletion) or intracellular insults (e.g., DNA damage) typically serve to attenuate CDK function. Although the signals that dictate commitment to the cell cycle are often cell type-specific, the core machinery that drives the cell cycle engine is well conserved.

31) Lee YM, Sicinski P Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human. Cell Cycle. 2006 Sep;5(18):2110-4. Epub 2006 Sep 15.

32) Malumbres M,, Barbacid M Cell cycle kinases in cancer. Curr Opin Genet Dev.2007 Feb;17(1):60-5.

Transitions into and within the mitotic cell cycle are dictated by the coordinate activation of cyclin-dependent kinase (CDK)/cyclin complexes, wherein cyclin binding

induces the catalytic activity of the kinase [Lee and Sicinski, 2006; Malumbres and Barbacid, 2007; Sherr, 1996; Sherr and Roberts, 2004]. Mitogenic signaling pathways generally induce cell cycle progression through ordered activation of CDK-cyclin complexes, whereas anti-mitogenic signals that result from extracellular events (e.g., nutrient depletion) or intracellular insults (e.g., DNA damage) typically serve to attenuate CDK function. Although the signals that dictate commitment to the cell cycle are often cell type-specific, the core machinery that drives the cell cycle engine is well conserved.


Lee, Y. M. and Sicinski, P. (2006) Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human Cell Cycle 5, 2110-4.

Malumbres, M. and Barbacid, M. (2007) Cell cycle kinases in cancer Curr Opin Genet Dev 17, 60-5.

Sherr, C. J. (1996) Cancer cell cycles Science 274, 1672-7.

Sherr, C. J. and Roberts, J. M. (2004) Living with or without cyclins and cyclin-dependent kinases Genes Dev 18, 2699-711.

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[22.] Rlm/Fragment 022 01 - Diskussion
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Prior to mitogenic stimulation cells can exit the cell cycle and enter into a resting stage deemed “G0. At this stage, several key gatekeepers of cell cycle transitions are invoked to prevent unscheduled cell cycle progression (33).

Figure 3:(from Balk et all2008) AR-cell cycle crosstalk.

Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21Cip1 and degradation of p27Kip1 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green.


33) Balk SP, Knudsen KE AR, the cell cycle, and prostate cancer. Nucl Recept Signal. 2008 Feb 1;6:e001.

[Page 2]

Prior to mitogenic stimulation cells can exit the cell cycle and

[Page 3]

enter into a resting stage deemed “G0”. At this stage, several key gatekeepers of cell cycle transitions are invoked to prevent unscheduled cell cycle progression.

[Page 4]

Figure 1. AR-cell cycle crosstalk. Activated AR stimulates the accumulation of cyclin D1 (D1), through mammalian Target of Rapamycin (mTOR), to activate CDK4 and promote phosphorylation of the retinoblastoma (RB) tumor suppressor. In addition, AR-induced expression of p21Cip1 and degradation of p27Kip1 further enhance cycD1/CDK4 and cycE/CDK2-dependent inactivation of RB and allow expression of E2F target genes like cyclin A (CycA). Cyclin A in turn activates CDK2 to drive G1-S phase transition. Subsequently engaged components of the cell cycle machinery then impinge on AR to regulate the androgen response. Elevated cyclin D1 acts as in a negative feedback loop to attenuate AR activity, thereby modulating androgen action. In G2-phase, CDK1 promotes the phosphorylation and activation of AR. However, AR is degraded in M-phase and is purposed to be a “licensing factor” for DNA replication. Components that suppress AR function are outlined in red, whereas positive effectors of AR activity are outlined in green.



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[23.] Rlm/Fragment 023 01 - Diskussion
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Mechanistic investigations have showed that AR plays a master regulation of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent-Kinase activity and finally, phosphorylation /inactivation of the receptor of the retinoblastoma tumor suppressor protein (34).

34) E. Cifuentes, R. Croxen, M Menon, E. R. Barrack, And G. Prem-Veer Reddy. Synchronized Prostate Cancer Cells for Studying Androgen Regulated Events in Cell Cycle Progression From G1 Into S Phase.. J Cell Physiol. 2003 Jun;195(3):337-45.

Mechanistic investigation has revealed that AR acts as a master regulator of G1-S phase progression, able to induce signals that promote G1 cyclin-dependent kinase (CDK) activity, induce phosphorylation/inactivation of the retinoblastoma tumor suppressor (RB), and thereby govern androgen-dependent proliferation.
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[24.] Rlm/Fragment 023 06 - Diskussion
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Like PR, the majority of identified phosphorylation sites for AR are located in the N-terminal domain. Although many of the NTD sites have been tested in vivo, assigning function to them has been difficult. Studies of transcriptional activation by AR on several androgen response elements containing promoters carried out in various cell lines has provided little information on the function of NTD sitespecific phosphorylation, Many phosphorylation mutants exhibited no aberrant activation characteristics when compared with wild type.(35,36,37,38). However, greater differences in activity can be detected when specific signaling pathways are activated or inhibited. For example, overexpression of cyclin D3/CDK11p58 inhibits AR activity by phosphorylating Ser308A mutant partially elevates hormone dependent activity and prevents cyclin D3/ CDK11p58- mediated repression of AR transcriptional activity (39).

35) Zhou, Z. X., Kemppainen, J. A., and Wilson, E. M. (1995) Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol. Endocrinol. 9, 605–615.

36) Zhu, Z., Becklin, R. R., Desiderio, D. M., and Dalton, J. T. (2001) Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochem. Biophys. Res. Commun. 284, 836–844.

37) Yang, C. S., Vitto, M. J., Busby, S. A., Garcia, B. A., Kesler, C. T., Gioeli, D., Shabanowitz, J., Hunt, D. F., Rundell, K., Brautigan, D. L., and Paschal, B. M. (2005) Simian virus 40 small t antigen mediates conformation- dependent transfer of protein phosphatase 2A onto the androgen receptor. Mol. Cell Biol. 25, 1298–1308.

38) Gioeli, D., Ficarro, S. B., Kwiek, J. J., Aaronson, D., Hancock, M., Catling, A. D., White, F. M., Christian, R. E., Settlage, R. E., Shabanowitz, J., Hunt, D. F., and Weber, M. J. (2002) Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J. Biol. Chem. 277, 29304–29314.].

39) Zong, H., Chi, Y., Wang, Y., Yang, Y., Zhang, L., Chen, H., Jiang, J., Li, Z., Hong, Y., Wang, H., Yun, X., and Gu, J. (2007) Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol. Cell Biol. 27, 7125–7142.

Like PR, the majority of identified phosphorylation sites for AR are located in the N-terminal domain (Figure 2). Although many of the NTD sites have been verified in vivo, assigning function to them has been difficult. Studies of transcriptional activation by AR of several androgen response elements containing promoters carried out in various cell lines has provided little information as to the function of NTD site-specific phosphorylation as many phosphorylation mutants have exhibited no aberrant activation characteristics when compared to wild type (56-60). However, greater differences in activity can be detected when specific signaling pathways are activated or inhibited. For example, overexpression of cyclin D3/CDK11p58 inhibits AR activity. The kinase phosphorylates Ser308; substitution of an alanine elevates hormone dependent activity modestly and prevents cyclin D3/ CDK11p58 mediated repression of AR transcriptional activity (61).

56. Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol. 1995; 9:605–615. [PubMed: 7565807]

57. Zhu Z, Becklin RR, Desiderio DM, Dalton JT. Identification of a novel phosphorylation site in human androgen receptor by mass spectrometry. Biochem Biophys Res Commun. 2001; 284:836– 844. [PubMed: 11396978]

58. Yang CS, Vitto MJ, Busby SA, Garcia BA, Kesler CT, Gioeli D, Shabanowitz J, Hunt DF, Rundell K, Brautigan DL, Paschal BM. Simian virus 40 small t antigen mediates conformation dependent transfer of protein phosphatase 2A onto the androgen receptor. Mol Cell Biol. 2005; 25:1298–1308. [PubMed: 15684382]

59. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 2002; 277:29304–29314. [PubMed: 12015328]

60. Chen S, Xu Y, Yuan X, Bubley GJ, Balk SP. Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1. Proc Natl Acad Sci U S A. 2006; 103:15969–15974. [PubMed: 17043241]

61. Zong H, Chi Y, Wang Y, Yang Y, Zhang L, Chen H, Jiang J, Li Z, Hong Y, Wang H, Yun X, Gu J. Cyclin D3/CDK11p58 complex is involved in the repression of androgen receptor. Mol Cell Biol. 2007; 27:7125–7142. [PubMed: 17698582]

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[25.] Rlm/Fragment 024 01 - Diskussion
Bearbeitet: 1. December 2014, 17:22 Singulus
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Several studies have suggested that AKT-mediated phosphorylation of Ser213 and Ser791 (numbered based on an AR length of 919 amino acids) reduces AR activity (40). Mutation of the AR Ser213 to alanine caused resistance to AKT-mediated suppression of activity in DU145 cells(41) . Palazzolo et al. found that substituting alanines for both of the sites also prevented AKT-mediated inhibition of AR transcriptional activity. Surprisingly, substitution of aspartic acids at either site blocked hormone binding and, therefore, ligand-dependent AR protein stabilization, ligand-mediated translocation, and AR transcriptional activity(42).

The remaining sites in the AR NTD domain also have been shown to have important functional roles. When a fragment of the androgen receptor (amino acids 507-660) is expressed, Ser515 and Ser578 are phosphorylated in response to EGF treatment(43).

The AR Ser515Ala mutation exhibited a more severe phenotype than the Ser578Ala and the double mutant displayed little to no activity; furthermore, EGF treatment had no effect on the activity of this mutant.


40) Wen, Y., Hu, M. C., Makino, K., Spohn, B., Bartholomeusz, G., Yan, D. H., and Hung, M. C. (2000) HER-2/neu promotes androgenindependent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 60, 6841–6845..

41) Taneja, S. S., Ha, S., Swenson, N. K., Huang, H. Y., Lee, P., Melamed, J., Shapiro, E., Garabedian, M. J., and Logan, S. K. (2005) Cell-specific regulation of androgen receptor phosphorylation in vivo. J. Biol. Chem. 280, 40916–40924..

42) Palazzolo, I., Burnett, B. G., Young, J. E., Brenne, P. L., La Spada, A. R., Fischbeck, K. H., Howell, B. W., and Pennuto, M. (2007) Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum. Mol. Genet. 16, 1593–1603.

43) Ponguta, L. A., Gregory, C. W., French, F. S., and Wilson, E. M. (2008) Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J. Biol. Chem. 283, 20989–21001.

Several studies have suggested that AKT mediated phosphorylation of Ser213 and Ser791 (numbered based on an AR length of 919 amino acids) reduces AR activity. Both sites are phosphorylated by the P13K/Akt signaling pathways (62-64). Mutation of the AR Ser213 to alanine caused AR to be resistant to AKT mediated suppression of activity in DU145 cells (64,65). Palazzolo et al found that substituting alanines for both of the sites also prevented

[page 7]

AKT mediated inhibition of AR transcriptional activity. Surprisingly, substitution of aspartic acids at either site blocked hormone binding and, therefore, ligand dependent AR protein stabilization, ligand-mediated translocation, and AR transcriptional activity (66).

The remaining sites in the AR NTD also have been shown to have important functional roles. When a fragment of the androgen receptor (amino acids 507-660) is expressed, Ser515 and Ser578 are phosphorylated in response to EGF treatment (67). The AR Ser515Ala mutation exhibited a more severe phenotype than the Ser578Ala and the double mutant displayed little to no activity; furthermore, EGF treatment had no effect on the activity of this mutant.


62. Wen Y, Hu MC, Makino K, Spohn B, Bartholomeusz G, Yan DH, Hung MC. HER-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway. Cancer Res. 2000; 60:6841–6845. [PubMed: 11156376]

63. Taneja SS, Ha S, Swenson NK, Huang HY, Lee P, Melamed J, Shapiro E, Garabedian MJ, Logan SK. Cell-specific regulation of androgen receptor phosphorylation in vivo. J Biol Chem. 2005; 280:40916–40924. [PubMed: 16210317]

64. Lin HK, Yeh S, Kang HY, Chang C. Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci U S A. 2001; 98:7200– 7205. [PubMed: 11404460]

65. Lin HK, Hu YC, Yang L, Altuwaijri S, Chen YT, Kang HY, Chang C. Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with different passage numbers. J Biol Chem. 2003; 278:50902– 50907. [PubMed: 14555644]

66. Palazzolo I, Burnett BG, Young JE, Brenne PL, La Spada AR, Fischbeck KH, Howell BW, Pennuto M. Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet. 2007; 16:1593–1603. [PubMed: 17470458]

67. Ponguta LA, Gregory CW, French FS, Wilson EM. Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J Biol Chem. 2008; 283:20989–21001. [PubMed: 18511414]

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[26.] Rlm/Fragment 025 01 - Diskussion
Bearbeitet: 17. November 2014, 22:04 Hindemith
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A Ser578Ala substitution results in increased nuclear localization of AR in the absence of ligand but eliminates AR transcriptional response to EGF. AR Ser578Ala also exhibits increased binding to Ku-70/80 regulatory subunits of DNA dependent protein kinase in addition to nuclear retention of the AR in association with hyperphosphorylation at Ser 515(44).

Finally, the Ser515Ala mutant is not phosphorylated on Ser650, which is located in the hinge region of AR (45).

One possible explanation for this effect is that phosphorylation at Ser515 mediates a conformational change of the AR thus making the Ser650 phosphosite either more available to phosphatases or less accessible to kinases. Attempting to assign function to the AR Ser650 phosphorylation site itself has produced conflicting reports. Early studies have suggested that blocking phosphorylation of this site resulted in 30% reduced activity with an MMTV-Luc reporter in CV1 cells . This was in direct contrast to later reports examining the function of Ser650 phosphorylation on AR activity in various cell lines using various reporters in which no phenotype was detected .


43) Ponguta, L. A., Gregory, C. W., French, F. S., and Wilson, E. M. (2008) Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration-recurrent prostate cancer. J. Biol. Chem. 283, 20989–21001.

44) Pierre Chymkowitch, Nicolas Le May, Pierre Charneau, Emmanuel Compe and Jean-Marc Egly. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J. 2011 Feb 2;30(3):468-79. Epub 2010 Dec 14

45) Wong, H. Y., Burghoorn, J. A., Van Leeuwen, M., De Ruiter, P. E., Schippers, E., Blok, L. J., Li, K. W., Dekker, H. L., De Jong, L., Trapman, J., Grootegoed, J. A., and Brinkmann, A. O. (2004) Phosphorylation of androgen receptor isoforms. Biochem. J. 383, 267–276.

A Ser578Ala substitution results in increased nuclear localization of AR in the absence of ligand but eliminates AR transcriptional response to EGF. AR Ser578Ala also exhibits increased binding to Ku-70/80 regulatory subunits of DNA-dependent protein kinase in addition to nuclear retention of the AR in association with hyperphosphorylation at Ser515 (67). Finally, the Ser515Ala mutant is not phosphorylated on Ser650, which is located in the hinge region of AR (68). One possible explanation for this is that phosphorylation at Ser515 mediates a conformational change of the AR thus making the Ser650 phospho site either more available to phosphatases or less accessible to kinases. Attempting to assign function to the AR Ser650 phosphorylation site itself has produced conflicting reports. Early studies have suggested that blocking phosphorylation of this site resulted in 30% reduced activity with an MMTV-Luc reporter in CV1 cells (56). This was in direct contrast to later reports examining the function of Ser650 phosphorylation on AR activity in various cell lines using various reporters in which no phenotype was detected (59,68).

56. Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol. 1995; 9:605–615. [PubMed: 7565807]

59. Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, White FM, Christian RE, Settlage RE, Shabanowitz J, Hunt DF, Weber MJ. Androgen receptor phosphorylation. Regulation and identification of the phosphorylation sites. J Biol Chem. 2002; 277:29304–29314. [PubMed: 12015328]

67. Ponguta LA, Gregory CW, French FS, Wilson EM. Site-specific androgen receptor serine phosphorylation linked to epidermal growth factor-dependent growth of castration recurrent prostate cancer. J Biol Chem. 2008; 283:20989–21001. [PubMed: 18511414]

68. Wong HY, Burghoorn JA, Van Leeuwen M, De Ruiter PE, Schippers E, Blok LJ, Li KW, Dekker HL, De Jong L, Trapman J, Grootegoed JA, Brinkmann AO. Phosphorylation of androgen receptor isoforms. Biochem J. 2004; 383:267–276. [PubMed: 15239671]

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[27.] Rlm/Fragment 026 01 - Diskussion
Bearbeitet: 1. December 2014, 17:24 Singulus
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However, careful examination of these studies revealed that the original observation by Zhuo et al. was evident at only high concentrations of receptor . Wong et al. also found that at high concentrations of receptor the Ser650Ala mutant is less active than wild type . AR Ser650 phosphorylation also plays an important role in nuclear export of AR in response to stress kinase signaling (29). A recent report has shown that protein phosphatase 1 (PP1) inhibition increases phosphorylation at AR Ser650 which causes a marked increase in nuclear export of AR which is not observed for the Ser650Ala mutant(46) .

This study suggests that PP1 plays a critical role in regulating AR protein stability and nuclear localization through dephosphorylation of AR at Ser650. In addition to Ser-Pro motifs, several tyrosine phosphorylation sites are present in the NTD of AR. A number of candidate sites have been identified in AR isolated from cells overexpressing Src. Based on the overall level of tyrosine phosphorylation in AR, substituting Phe for Tyr534 reduced the Tyr phosphorylation most substantially suggesting that this is a major site under these conditions(47).


29)Daniel Gioeli, Ben E. Black, Vicki Gordon, Adam Spencer, Cristina T. Kesler, Scott T. Eblen, Bryce M. Paschal, and Michael J. Weber. Stress Kinase Signaling Regulates Androgen Receptor Phosphorylation, Transcription, and Localization Mol Endocrinol. 2006 Mar;20(3):503-15. Epub 2005 Nov 10

46) Chen, S., Kesler, C. T., Paschal, B. M., and Balk, S. P. (2009) Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. J. Biol. Chem. 284, 25576–25584.

47) Guo, Z., Dai, B., Jiang, T., Xu, K., Xie, Y., Kim, O., Nesheiwat, I., Kong, X., Melamed, J., Handratta, V. D., Njar, V. C., Brodie, A. M., Yu, L. R., Veenstra, T. D., Chen, H., and Qiu, Y. (2006) Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 10, 309–319.].

However, careful examination of these studies revealed that the original observation by Zhuo et al was evident at only high concentrations of receptor (56). Wong et al also found that at high concentrations of receptor the Ser650Ala mutant is less active than wild type (68). AR Ser650 phosphorylation also plays an important role in nuclear export of AR in response to stress kinase signaling (69). A recent report has shown that protein phosphatase 1 (PP1) inhibition increases phosphorylation at AR Ser650 which causes a marked increase in nuclear export of AR which is not observed for the Ser650Ala mutant (70). This study suggests that PP1 plays a critical role in regulating AR protein stability and nuclear localization through dephosphorylation of AR at Ser650.

In addition to Ser-Pro motifs, several tyrosine phosphorylation sites are present in the NTD of AR. A number of candidate sites have been identified in AR isolated from cells overexpressing Src. Based on the overall level of tyrosine phosphorylation in AR, substituting Phe for Tyr534 reduced the Tyr phosphorylation most substantially suggesting that this is a major site under these conditions (71).


56. Zhou ZX, Kemppainen JA, Wilson EM. Identification of three proline-directed phosphorylation sites in the human androgen receptor. Mol Endocrinol. 1995; 9:605–615. [PubMed: 7565807]

68. Wong HY, Burghoorn JA, Van Leeuwen M, De Ruiter PE, Schippers E, Blok LJ, Li KW, Dekker HL, De Jong L, Trapman J, Grootegoed JA, Brinkmann AO. Phosphorylation of androgen receptor isoforms. Biochem J. 2004; 383:267–276. [PubMed: 15239671]

69. Gioeli D, Black BE, Gordon V, Spencer A, Kesler CT, Eblen ST, Paschal BM, Weber MJ. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol. 2006; 20:503–515. [PubMed: 16282370]

70. Chen S, Kesler CT, Paschal BM, Balk SP. Androgen receptor phosphorylation and activity are regulated by an association with protein phosphatase 1. J Biol Chem. 2009

71. Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, Nesheiwat I, Kong X, Melamed J, Handratta VD, Njar VC, Brodie AM, Yu LR, Veenstra TD, Chen H, Qiu Y. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006; 10:309–319. [PubMed: 17045208]

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[28.] Rlm/Fragment 027 01 - Diskussion
Bearbeitet: 1. December 2014, 17:25 Singulus
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The Tyr534Phe mutant also exhibited reduced activity and DNA binding at low doses of ligand and defective nuclear translocation in response to various stimuli . Finally, Tyr534Phe mutant expression caused growth inhibition in both cell lines and tumor xenografts containing the Tyr534Phe mutant grew more slowly than tumors expressing WT AR in castrated mice, thereby demonstrating a role for Tyr534 phosphorylation in prostate cancer cell growth under androgen-depleted conditions. Two additional tyrosine phosphorylation sites have been identified in cells treated with heregulin or transfected with constitutively active Ack (Cdc42 associated kinase).

Mutation of these sites, Tyr267 and Tyr363 to phenylalanine (Tyr267Phe and Tyr363Phe, respectively), reduced Ackinduced reporter activation and recruitment to the enhancer, thus demonstrating the importance of these sites in AR basal and liganddependent activity as well as in potentiation of AR activity by kinase signaling. In addition, substituting Phe at both of these sites also reduced tumor growth of Ack-driven tumor xenografts in castrated nude mice.

The Tyr534Phe mutant also exhibited reduced activity and DNA binding at low doses of ligand and defective nuclear translocation in response to various stimuli (71). Finally, Tyr534Phe mutant expression caused growth inhibition in both cell lines and tumor xenografts containing the Tyr534Phe mutant grew more slowly than tumors expressing WT AR in castrated mice, thereby demonstrating a role for Tyr534 phosphorylation in prostate cancer cell growth under androgen-depleted conditions (71). Two additional tyrosine phosphorylation sites have been identified in cells treated with heregulin or transfected with constitutively active Ack (Cdc42 associated kinase) (72). Mutation of these sites, Tyr267 and Tyr363 to phenylalanine (Tyr267Phe and Tyr363Phe, respectively), reduced Ack-induced reporter activation and recruitment to the enhancer, thus demonstrating the importance of these sites in AR basal and liganddependent activity as well as in potentiation of AR activity by kinase signaling (72). In addition, substituting Phe at both of these sites also reduced tumor growth of Ack-driven tumor xenografts in castrated nude mice (72).

71. Guo Z, Dai B, Jiang T, Xu K, Xie Y, Kim O, Nesheiwat I, Kong X, Melamed J, Handratta VD, Njar VC, Brodie AM, Yu LR, Veenstra TD, Chen H, Qiu Y. Regulation of androgen receptor activity by tyrosine phosphorylation. Cancer Cell. 2006; 10:309–319. [PubMed: 17045208]

72. Mahajan NP, Liu Y, Majumder S, Warren MR, Parker CE, Mohler JL, Earp HS, Whang YE. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proc Natl Acad Sci U S A. 2007; 104:8438–8443. [PubMed: 17494760]

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[29.] Rlm/Fragment 028 01 - Diskussion
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Recently has been demonstrated that Androgen receptor (AR) interacts with β-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. Pin1 is a peptidyl-prolyl cis/trans isomerase that stabilizes β-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3β (GSK-3β)-dependent degradation. Higher Pin1 expression in primary PCa is correlated with disease recurrence, and this study found that Pin1 expression was markedly increased in metastatic PCa.(48).

48) Shao-Yong Chen, Gerburg Wulf,Xiao Zhen Zhou,Mark A. Rubin, Kun Ping Lu, and Steven P. Balk .Activation of "-Catenin Signaling in Prostate Cancer by Peptidyl-Prolyl Isomerase Pin1-Mediated Abrogation of the Androgen Receptor–"-Catenin Interaction. Mol Cell Biol. 2006 Feb;26(3):929-39

Androgen receptor (AR) interacts with β-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. Pin1 is a peptidyl-prolyl cis/trans isomerase that stabilizes β-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3β (GSK-3β)-dependent degradation. Higher Pin1 expression in primary PCa is correlated with disease recurrence, and this study found that Pin1 expression was markedly increased in metastatic PCa.
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[30.] Rlm/Fragment 030 01 - Diskussion
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Erstellt: 3. November 2014, 12:55 (Hindemith)
Bao et al 2004, Fragment, Gesichtet, Rlm, SMWFragment, Schutzlevel sysop, Verschleierung

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Pin1 is normally expressed at very low levels in most normal tissues, although significant levels of Pin1 are often found in cell types that normally undergo active cell division. Pin1 is overexpressed in some human malignancies and that its expression closely correlates with the level of cyclin D1 in human breast cancer (54).

54) Wulf, G. M., Ryo, A., Wulf, G. G., Lee, S. W., Niu, T., and Lu, K. P. Pin1 is overexpressed in breast cancer and potentiates the transcriptional activity of phosphorylatedc-Jun towards the cyclin D1 gene. EMBO J., 20: 3459–3472, 2001.

Recently, it has been reported that Pin1 is overexpressed in human breast cancer cell lines and breast cancer tissues, and its expression closely correlates with the level of cyclin D1 in tumors.15

[page 1731]

These results indicate that Pin1 is normally expressed at very low levels in most normal tissues, although significant levels of Pin1 are often found in cell types that normally undergo active cell division.


15. Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Lu KP: Pin1 is overexpressed in breast cancer and potentiates the transcriptional activity of phosphorylated c-Jun towards the cyclin D1 gene. EMBO J 2001, 20:3459–3472

Anmerkungen

The source is not mentioned.

Sichter
(Hindemith), SleepyHollow02

[31.] Rlm/Fragment 030 Fig4 - Diskussion
Bearbeitet: 10. December 2014, 23:33 Singulus
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Fig 4: The different roles of PIN1 in cellular physiology Fig. 1. The different roles of PIN1 in cellular physiology
Anmerkungen

Identical, no source given. Continued on next page (see [Rlm/Fragment_031_01]).

Sichter
(Graf Isolan) Singulus

[32.] Rlm/Fragment 031 01 - Diskussion
Bearbeitet: 4. December 2014, 21:04 Singulus
Erstellt: 3. December 2014, 13:51 (Graf Isolan)
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PIN1 is a member of the evolutionarily conserved peptidylprolyl isomerase (PPIase) family of proteins. PIN1 has a two-domain structure that consists of an N-terminal WW domain (amino acids 1–39) and the Cterminal PPIase domain (amino acids 45–163). The WW domain binds only to specific pSer/Thr-Pro-motifs and the PPIase isomerase domain catalyzes the conformational switch from cis to trans of target proteins. This fact is especially important because Pro-directed kinases and phosphatases are conformation-specific and act only on the trans isoform (55,56). For this reason, PIN1 is important for many physiological activities of the cell (Fig. 4).

In cell cycle control, PIN1 was originally identified and defined as a protein important in mitosis (57).

Depletion of PIN1 in yeast and human cells induces mitotic arrest and its over-expression blocks the cells in the G2 phase of the cell cycle (51). Since the discovery of PIN1, a plethora of protein targets have been discovered, many of which are involved in the G0 and G1/S control (58). PIN1 controls Cyclin D1 mRNA levels and it is involved in regulation of CyclinD1, c-MYC and Cyclin E protein stability. PIN1 -/- MEF showed proliferative defects in cell cycle entry after serum deprivation. In addition, PIN1 is a target of E2F transcription factors and its mRNA and protein levels fluctuate during cell cycle [(59).]


51)Lu, K. P., Hanes, S. D., and Hunter, T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature (Lond.), 380: 544–547, 1996.

55) Lu, K.P., et al., Prolyl cistrans isomerization as a molecular timer. Nat Chem Biol, 2007. 3(10): p. 619‐29.

56) Lu, K.P. and X.Z. Zhou, The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol, 2007. 8(11): p. 904‐16.

57) Shen, M., et al., The essential mitotic peptidylprolyl isomerase Pin1 binds and regulates mitosisspecific phosphoproteins. Genes Dev, 1998. 12(5): p. 706‐20.

58) Yeh, E.S. and A.R. Means, PIN1, the cell cycle and cancer. Nat Rev Cancer, 2007. 7(5): p. 381‐8.

59) Ryo, A., et al., PIN1 is an E2F target gene essential for Neu/Rasinduced [sic] transformation of mammary epithelial cells. Mol Cell Biol, 2002. 22(15): p. 5281‐95.

[Page 29]

PIN1 is a member of the evolutionarily conserved peptidylprolyl isomerase (PPIase) family of proteins. PIN1 has a two-domain structure that consists of an N-terminal WW domain (amino acids 1–39) and the Cterminal PPIase domain (amino acids 45–163). The WW domain binds only to specific pSer/Thr-Pro-motifs and the PPIase isomerase domain catalyzes the conformational switch from cis to trans of target proteins. This fact is especially important because Pro-directed kinases and phosphatases are conformation-specific and act only on the trans isoform [3, 4]. For this reason, PIN1 is important for many physiological activities of the cell (Fig. 1).

[Page 30]

In cell cycle control, PIN1 was originally identified and defined as a protein important in mitosis. Many of PIN1’s substrates contain a single phosphorylation target in the form of CDC25, WEE1 and RPB1[15]. Others, like CK2 and Sil, have multi-phosphorylation sites, suggesting a different mechanism in PIN1 function [16, 17]. Depletion of PIN1 in yeast and human cells induces mitotic arrest and its over-expression blocks the cells in the G2 phase of the cell cycle [14]. Since the discovery of PIN1, a plethora of protein targets have been discovered, many of which are involved in the G0 and G1/S control [11]. Evidence emerged from in vitro and in vivo animal models. PIN1 controls Cyclin D1 mRNA levels and it is involved in regulation of CyclinD1, c-MYC and Cyclin E protein stability [5, 11]. PIN1 -/- MEF showed

[Page 31]

proliferative defects in cell cycle entry after serum deprivation. In addition, PIN1 is a target of E2F transcription factors and its mRNA and protein levels fluctuate during cell cycle [18].


3. Lu, K.P., et al., Prolyl cistrans isomerization as a molecular timer. Nat Chem Biol, 2007. 3(10): p. 619‐29.

4. Lu, K.P. and X.Z. Zhou, The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol, 2007. 8(11): p. 904‐16.

11. Yeh, E.S. and A.R. Means, PIN1, the cell cycle and cancer. Nat Rev Cancer, 2007. 7(5): p. 381‐8.

14. Lu, K.P., S.D. Hanes, and T. Hunter, A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature, 1996. 380(6574): p. 544‐7.

15. Shen, M., et al., The essential mitotic peptidylprolyl isomerase Pin1 binds and regulates mitosisspecific phosphoproteins. Genes Dev, 1998. 12(5): p. 706‐20.

16. Messenger, M.M., et al., Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions. J Biol Chem, 2002. 277(25): p. 23054‐64.

17. Campaner, S., et al., Sil phosphorylation in a Pin1 binding domain affects the duration of the spindle checkpoint. Mol Cell Biol, 2005. 25(15): p. 6660‐72.

18. Ryo, A., et al., PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells. Mol Cell Biol, 2002. 22(15): p. 5281‐95.

Anmerkungen

Although identical, nothing has been marked as a citation.

Starting with reference 55), again the formatting of references changes in Rlm so that it becomes exactly like that of the unnamed source.

"Neu/Rasinduced" (missing hyphen) is a copy-and-paste-mistake.

Sichter
(Graf Isolan), SleepyHollow02

[33.] Rlm/Fragment 032 01 - Diskussion
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Even in cancer pathology, PIN1 over-expression was found in 38 different tumour types out of 60, including most common human cancers such as prostate, cervical, brain, ovary, lung, breast, liver cancer, and melanoma . In cancer pathology, PIN1 over-expression was found in 38 different tumour types out of 60, including most common human cancers such as prostate, cervical, brain, ovary, lung, breast, liver cancer, and melanoma [8].

8. Bao, L., et al., Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am J Pathol, 2004. 164(5): p. 1727‐37.

Anmerkungen

Although identical, nothing has been marked as a citation. Continued from previous page.

Sichter
(Graf Isolan), SleepyHollow02

[34.] Rlm/Fragment 032 04 - Diskussion
Bearbeitet: 3. December 2014, 07:51 Singulus
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Pin1 overexpression has been observed in a subset of primary prostate cancers, and its expression correlates with increased risk of recurrence after radical prostatectomy (60).

60) Abate-Shen, C., and Shen, M. M. Molecular genetics of PCa. Genes Dev., 14: 2410–2434, 2000.

Significantly, Pin1 overexpression has also been observed in a subset of primary prostate cancers, and its expression correlates with increased risk of recurrence after radical prostatectomy (2).

2. Ayala, G., D. Wang, G. Wulf, A. Frolov, R. Li, J. Sowadski, T. M. Wheeler, K. P. Lu, and L. Bao. 2003. The prolyl isomerase Pin1 is a novel prognostic marker in human prostate cancer. Cancer Res. 63:6244–6251.

Anmerkungen

Nothing has been marked as a citation.

Sichter
(Graf Isolan), SleepyHollow02

[35.] Rlm/Fragment 032 14 - Diskussion
Bearbeitet: 4. December 2014, 21:02 Singulus
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Increased expression of Pin1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice (48). However, the functional effects of Pin1 overexpression on β-catenin nuclear signaling in PCa cells (and in particular in PTEN-deficient cells), and how it contributes to more aggressive biological behavior have not been determined.

48) Shao-Yong Chen, Gerburg Wulf,Xiao Zhen Zhou,Mark A. Rubin, Kun Ping Lu, and Steven P. Balk .Activation of "-Catenin Signaling in Prostate Cancer by Peptidyl-Prolyl Isomerase Pin1-Mediated Abrogation of the Androgen Receptor–"-Catenin Interaction. Mol Cell Biol. 2006 Feb;26(3):929-39

However, the functional effects of Pin1 overexpression on β-catenin nuclear signaling in PCa cells (and in particular in PTEN-deficient cells), and how it contributes to more aggressive biological behavior have not been determined.

[...] Consistent with this result, increased expression of Pin1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice.

Anmerkungen

Nothing has been marked as a citation.

Sichter
(Graf Isolan), SleepyHollow02

[36.] Rlm/Fragment 033 02 - Diskussion
Bearbeitet: 6. December 2014, 20:06 Singulus
Erstellt: 5. December 2014, 13:52 (Graf Isolan)
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It is now clear that Pin1plays [sic] a catalytic role in oncogenesis in solid cancers. [...] RYO et al. have already suggested PIN1 like a good target for patients with prostate cancer with different kind of experiments. In those studies a retrovirus-mediated RNA interference targeting Pin1was [sic] expressed in PC3 and LNCaP cells, and cell growth and several transformed properties were investigated.

As result the stable expression of Pin1-specific small interfering RNA constructs in PC3 and LNCaP cells significantly reduced cellular proliferation, colony formation, migration, and invasion but strongly enhanced the apoptotic response induced by serum depletion or treatment with anticancer agents. Furthermore, Pin1depletion [sic] significantly suppressed tumorigenic potential in athymicmice [sic], resulting in the inhibition of both tumor growth and angiogeneisis.

These results strongly suggest that Pin1plays [sic] an important role not only in tumorigenesis but also in the maintenance of the transformed phenotype in prostate cancer cells.

Abstract

Purpose: The peptidyl-prolyl isomrase Pin1plays [sic] a catalytic role in oncogenesis in solid cancers, including prostate cancer. [...]

Experimental Design: A retrovirus-mediated RNA interference targeting Pin1was [sic] expressed in PC3 and LNCaP cells, and cell growth and several transformed properties were investigated.

Results: The stable expression of Pin1-specific small interfering RNA constructs in PC3 and LNCaPce lls significantly reduced cellular proliferation, colony formation, migration, and invasion but strongly enhanced the apoptotic response induced by serum depletion or treatment with anticancer agents. Furthermore, Pin1depletion [sic] significantly suppressed tumorigenic potential in athymic mice, resulting in the inhibition of both tumor growth and angiogeneisis.

Conclusions: These results strongly suggest that Pin1plays [sic] an important role not only in tumorigenesis but also in the maintenance of the transformed phenotype in prostate cancer cells.

Anmerkungen

Although identical, nothing has been marked as a citation.

Though "RYO et al." is named as some kind of reference, the article, where this passage comes from, is not to be found in Rlm's list of references.

Sichter
(Graf Isolan), SleepyHollow02

[37.] Rlm/Fragment 035 09 - Diskussion
Bearbeitet: 4. December 2014, 21:09 Singulus
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In a GST gene fusion system, the GST sequence is incorporated into an expression vector alongside the gene sequence encoding the protein of interest. Induction of protein expression from the vector's promoter results in expression of a fusion protein. This GST-fusion protein can then be purified from cells via its high affinity for glutathione. It is fused to the N-terminus of a protein. Agarose beads can be coated with glutathione, and such glutathione-Agarose beads bind GST-proteins. These beads are then washed, to remove contaminating bacterial proteins. In a GST gene fusion system, the GST sequence is incorporated into an expression vector alongside the gene sequence encoding the protein of interest. Induction of protein expression from the vector's promoter results in expression of a fusion protein. This GST-fusion protein can then be purified from cells via its high affinity for glutathione. It is fused to the N-terminus of a protein. Agarose beads can be coated with glutathione, and such glutathione-Agarose beads bind GST-proteins. These beads are then washed, to remove contaminating bacterial proteins.
Anmerkungen

Although identical, nothing has been marked as a citation. No source given.

Sichter
(Graf Isolan), SleepyHollow02

[38.] Rlm/Fragment 036 02 - Diskussion
Bearbeitet: 4. December 2014, 22:00 Singulus
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Fig:5a Possible site of ineraction between Pin1 and AR

Fig5b: In vitro and in vivo interaction between PIN1 and AR a) Potential PIN1 binding site targets in AR protein. b) GST-PIN1 interaction with AR. A specific band was detected in the GST-PIN1 lane and no band is detected in GST control lane.

Fig. 6. In vitro and in vivo interaction between PIN1 and pRb. a) Potential PIN1 binding site targets in pRb protein. b) GST-PIN1 interaction with pRb. A specific band was detected in the GST-PIN1 lane and no band is detected in GST control lane. Of note, the band corresponds to the high molecular weight of phospho-pRb. As a control, the membrane was

probed with anti GST antibody.

Anmerkungen

Slightly adapted to the case at hand; still, nothing has been marked as a citation. The "blind" take-over of text leads to a confusing legend (what does the "a)" stand for in the legend of "Fig5b"?). Continued on the following page.

Sichter
(Graf Isolan), SleepyHollow02

[39.] Rlm/Fragment 037 04 - Diskussion
Bearbeitet: 5. December 2014, 18:59 Singulus
Erstellt: 4. December 2014, 13:05 (Graf Isolan)
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To assess the in vivo interaction between PIN1 and AR, LNCaP cells were immunoprecipitated with anti-PIN1 antibody and analyzed by western blot with anti-AR antibody. [...]

Co-immunoprecipitation is a purification procedure to determine if two different proteins interact. An antibody specific to the protein of interest is added to a cell lysate. Then the antibody-protein complex is pelleted usually using protein-A/G agarose, which binds most antibodies. If there are any proteins that bind to the first protein, they will also be pelleted. Identification of proteins in the pellet can be determined by western blot.

To assess the in vivo interaction between PIN1 and pRb, T98G cells were immunoprecipitated with anti-PIN1 antibody and analyzed by western blot with anti-pRb antibody.

Co-immunoprecipitation is a purification procedure to determine if two different proteins interact. An antibody specific to the protein of interest is added to a cell lysate. Then the antibody-protein complex is pelleted usually using protein-A/G agarose, which binds most antibodies. If there are any proteins that bind to the first protein, they will also be pelleted. Identification of proteins in the pellet can be determined by western blot.

Anmerkungen

Slightly adapted to the situation at hand, but otherwise identical. Nothing has been marked as a citation.

Sichter
(Graf Isolan), SleepyHollow02

[40.] Rlm/Fragment 043 09 - Diskussion
Bearbeitet: 6. December 2014, 20:09 Singulus
Erstellt: 5. December 2014, 11:54 (Graf Isolan)
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Recently Gioeli et.al found an association between (CDK)9 and AR. CDK9 phosphorylates the AR on Ser81 in vitro. Phosphorylation is specific to AR Ser81 because CDK9 did not phosphorylate the AR on other serine phosphorylation sites. Overexpression of CDK9 with its cognate cyclin, Cyclin T, increased Ser81 phosphorylation levels in cells. Small interfering RNA knockdown of CDK9 protein levels decreased hormone-induced S81 phosphorylation. Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced [Ser81 phosphorylation further, suggesting that CDK9 regulates Ser81 phosphorylation.] We observed cyclin-dependent kinase (CDK)9 association with the AR. CDK9 phosphorylates the AR on S81 in vitro. Phosphorylation is specific to S81 because CDK9 did not phosphorylate the AR on other serine phosphorylation sites. Overexpression of CDK9 with its cognate cyclin, Cyclin T, increased S81 phosphorylation levels in cells. Small interfering RNA knockdown of CDK9 protein levels decreased hormone-induced S81 phosphorylation. Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced S81 phosphorylation further, suggesting that CDK9 regulates S81 phosphorylation.
Anmerkungen

Although nearly identical, nothing has been marked as a citation. It is not clear which work of Gioeli Rlm refers to. Is this vagueness intentional?

Gioeli is one of the co-authors of Gordon et al 2010.

Sichter
(Graf Isolan), SleepyHollow02

[41.] Rlm/Fragment 044 01 - Diskussion
Bearbeitet: 6. December 2014, 20:08 Singulus
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[Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced] Ser81 phosphorylation further, suggesting that CDK9 regulates Ser81 phosphorylation. Pharmacological inhibition of CDK9 also resulted in decreased AR transcription in LNCaP cells. Collectively these results suggest that CDK9 phosphorylation of AR Ser81 is an important step in regulating AR transcriptional activity and prostate cancer cell growth. Additionally, treatment of LNCaP cells with the CDK9 inhibitors, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole and Flavopiridol, reduced S81 phosphorylation further, suggesting that CDK9 regulates S81 phosphorylation. Pharmacological inhibition of CDK9 also resulted in decreased AR transcription in LNCaP cells. Collectively these results suggest that CDK9 phosphorylation of AR S81 is an important step in regulating AR transcriptional activity and prostate cancer cell growth.
Anmerkungen

Continues from the previous page. Although nearly identical, nothing has been marked as a citation.

Gioeli is one of the co-authors of Gordon et al 2010.

Sichter
(Graf Isolan), SleepyHollow02

[42.] Rlm/Fragment 047 01 - Diskussion
Bearbeitet: 1. December 2014, 17:27 Singulus
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Discussion

The fundamental clinical problem for disseminated prostate cancer is the transition of androgen dependent desease [sic] to androgen independent desease [sic] after androgen ablation therapy. Collectively, data suggest that although advanced prostate cancer may be functionally independent of physiologic levels of androgen, it is not independent of the AR.

DISCUSSION

The fundamental clinical problem for disseminated prostate cancer is the transition of androgen-dependent disease to androgen-independent disease after androgen ablation therapy. Collectively, data suggest that although advanced prostate cancer may be functionally independent of physiologic levels of androgen, it is not independent of the AR (10, 12, 13, 23).


[...]

Anmerkungen

The source is not mentioned here.

Sichter
(Hindemith), SleepyHollow02

[43.] Rlm/Fragment 049 01 - Diskussion
Bearbeitet: 8. February 2015, 20:46 Schumann
Erstellt: 3. November 2014, 12:33 (Hindemith)
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[It is well known that one major regulatory] mechanism in cell proliferation and transformation is phosphorylation of proteins on serine or threonine residues preceding proline (pSer/Thr- Pro) by various prodirected protein kinases, such as MAP kinases, cyclin-dependent kinases, JNK, and GSK3β. Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is normally restrained by phosphorylation, but catalyzed specifically by the essential prolyl isomerase Pin1. By isomerizing pSer81, Pin1 induce conformational changes in androgen receptor. This, phosphorylation- dependent prolyl isomerization is a critical mechanism in phosphorylation signaling. One major regulatory mechanism in cell proliferation and transformation is phosphorylation of proteins on serine or threonine residues preceding proline (pSer/Thr- Pro) by various prodirected protein kinases, such as MAP kinases, cyclin-dependent kinases, JNK, and GSK3β.1–3 Interestingly, the pSer/Thr-Pro motifs in proteins exist in two completely distinct cis and trans conformations, whose conversion is normally restrained by phosphorylation, but catalyzed specifically by the essential prolyl isomerase Pin1.3–6 By isomerizing specific pSer/Thr-Pro bonds, Pin1 has been shown to catalytically induce conformational changes in proteins after phosphorylation, thereby having profound effects on their catalytic activity, dephosphorylation, protein-protein interactions, subcellular location, and/or turnover.4,5,7–18 Thus, phosphorylation- dependent prolyl isomerization is a critical postphosphorylation regulatory mechanism in phosphorylation signaling.3

[...]

Anmerkungen

The source is not mentioned.

Sichter
(Hindemith), SleepyHollow02

[44.] Rlm/Fragment 049 11 - Diskussion
Bearbeitet: 1. December 2014, 17:29 Singulus
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Diverse agonists including activators of protein kinase A (forskolin) and protein kinase C [phorbol-12-myristate-13-acetate (PMA)] increased Ser 650 phosphorylation. Ser 650 phosphorylation occurs by both hormone-dependent and hormone- independent mechanisms (androgen, protein kinase A, EGF, and protein kinase C) suggest that modification of this site might be used to regulate steroid receptor function in response to a variety of physiological stimuli. Gioeli et al. have investigated which signal transduction pathways regulate Ser 650 phosphorylation and determined the effect of these signaling pathways on AR function. Notably, diverse agonists

[page 504]

including activators of protein kinase A (forskolin) and protein kinase C [phorbol-12-myristate-13-acetate (PMA)] increased Ser 650 phosphorylation (15). [...] The fact that Ser 650 phosphorylation occurs by both hormone-dependent and hormone-independent mechanisms (androgen, protein kinase A, EGF, and protein kinase C) suggest that modification of this site might be used to regulate steroid receptor function in response to a variety of physiological stimuli.

[...] In this study, we have investigated which signal transduction pathways regulate Ser 650 phosphorylation and determined the effect of these signaling pathways on AR function.

Anmerkungen

The source is mentioned in the text, but not in a way that suggests to the reader that even the text before is taken from it literally.

Sichter
(Hindemith), SleepyHollow02

[45.] Rlm/Fragment 054 11 - Diskussion
Bearbeitet: 5. December 2014, 19:02 Singulus
Erstellt: 5. December 2014, 00:26 (Graf Isolan)
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Lentiviral production

To generate knock down cells, lentiviral particles were produced as described

(http://www.broadinstitute.org/genome_bio/trc/publicProtocols.html).

Briefly, 1x106 293FT cells (Invitrogen Corp, Carlsbad, CA, USA) were transfected with 2.25 μg of PAX2 packaging plasmid, 0.75 μg of PMD2G envelop plasmid and 3μg of pLKO.1 hairpin vector utilizing [30 μl of Fugene HD (Roche Applied Science, Indianapolis, IN, USA) in 10 cm plate.]

Lentiviral production

To generate knock down cells, lentiviral particles were produced as described (http://www.broadinstitute.org/genome_bio/trc/publicProtocols.html). Briefly, 1x106 293FT cells (Invitrogen Corp, Carlsbad, CA, USA) were transfected with 2.25 μg of PAX2 packaging plasmid, 0.75 μg of PMD2G envelop plasmid and 3μg of pLKO.1 hairpin vector utilizing 30 μl of Fugene HD (Roche Applied Science, Indianapolis, IN, USA) in 10 cm plate.

Anmerkungen

Although identical, nothing has been marked as a citation. Continued on the next pages.

Sichter
(Graf Isolan), SleepyHollow02

[46.] Rlm/Fragment 055 01 - Diskussion
Bearbeitet: 5. December 2014, 19:04 Singulus
Erstellt: 5. December 2014, 09:56 (Graf Isolan)
Fragment, Gesichtet, Rizzolio 2010, Rlm, SMWFragment, Schutzlevel sysop, Verschleierung

Typus
Verschleierung
Bearbeiter
Graf Isolan
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 55, Zeilen: 1-2, 4-8, 10-18
Quelle: Rizzolio 2010
Seite(n): 60-61, 65, Zeilen: 60:14-18.19-21 - 61:1-2; 65:3-11
[Briefly, 1x106 293FT cells (Invitrogen Corp, Carlsbad, CA, USA) were transfected with 2.25 μg of PAX2 packaging plasmid, 0.75 μg of PMD2G envelop plasmid and 3μg of pLKO.1 hairpin vector utilizing] 30 μl of Fugene HD (Roche Applied Science, Indianapolis, IN, USA) in 10 cm plate. Polyclonal populations of Pin1 kd and scrambled cells were generated by infection with 1 MOI (multiplicity of infectious) of shRNA lentiviral particles. 2.5x105 cells were plated in a multi 6 wells plate. The day after, the cells were transduced with 1 MOI of lentiviral particle in 10% FBS MEM medium. After 3 days post-infection, the cells were selected with 2 μg/ml of puromycin (Sigma-Aldrich, St Louis, MO, USA) for 1 week [sic]

Pull-down analyses

GST and GST-Pin1 proteins were produced in BL21 bacteria cells. Cells were grown to mid log phase and then induced to express protein by adding 0.25mM of isopropyl-1-thio-b-D-galactopyranoside (IPTG, Roche Applied Science, Indianapolis, IN, USA). The cultures were shaken for 4 h; bacteria were then pelleted and resuspended in NENT buffer (20mM Tris (pH 8), 100mM NaCl, 1mM ethylenediaminetetraacetic acid (EDTA), 0.5% NP-40). Cell suspensions were sonicated and pelleted so that the supernatant could be collected.

[Page 60]

Briefly, 1x106 293FT cells (Invitrogen Corp, Carlsbad, CA, USA) were transfected with 2.25 μg of PAX2 packaging plasmid, 0.75 μg of PMD2G envelop plasmid and 3μg of pLKO.1 hairpin vector utilizing 30 μl of Fugene HD (Roche Applied Science, Indianapolis, IN, USA) in 10 cm plate. The lentivirus were collected and filtered (45um) after 48 hours. 2.5x105 T98G cells were plated in a multi 6 wells plate. The following day, the cells were transduced with 1 MOI of lentiviral particle in 10% FBS DMEM medium. After 3 days post-infection, the

[Page 61]

cells were selected with 2 μg/ml of puromycin (Sigma-Aldrich, St Louis, MO, USA) for 1 week.

[Page 65]

GST and GST-PIN1 proteins were produced in BL21 bacteria cells. Cells were grown to mid log phase and then induced to express protein by adding 0.25mM of isopropyl-1-thio-b-D-galactopyranoside (IPTG, Roche Applied Science, Indianapolis, IN, USA). The cultures were shaken for 4 h; bacteria were then pelleted and resuspended in NENT buffer (20mM Tris (pH 8), 100mM NaCl, 1mM ethylenediaminetetraacetic acid (EDTA), 0.5% NP-40). Cell suspensions were sonicated and pelleted so that the supernatant could be collected.

Anmerkungen

Although nearly identical, nothing has been marked as a citation. Continued from previous page.

Sichter
(Graf Isolan), SleepyHollow02

[47.] Rlm/Fragment 056 01 - Diskussion
Bearbeitet: 5. December 2014, 19:06 Singulus
Erstellt: 5. December 2014, 10:05 (Graf Isolan)
Fragment, Gesichtet, Rizzolio 2010, Rlm, SMWFragment, Schutzlevel sysop, Verschleierung

Typus
Verschleierung
Bearbeiter
Graf Isolan
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 56, Zeilen: 1-15
Quelle: Rizzolio 2010
Seite(n): 65-66, Zeilen: 65:11-17.(17-19).20-22 - 66:1-5
The remaining bacteria were then resuspended in NENT buffer plus 2% of N-lauryl-sarcosine, then pelleted and finally, the supernatants were collected again. The combined supernatants were incubated with glutathione agarose beads (Sigma Inc., St Louis, MO, USA) overnight at 4 oC. The agarose was then pelleted and washed three times in NENT buffer. The GST protein was analyzed by electrophoresis gel and blue coomassie staining. 1mg of protein was pulled-down with 10 ug of GST or GST-Pin1.

Co-immunoprecipitation assay

Sub-confluent LNcaP cells were harvested and proteins were prepared as follows: the cell pellet was resuspended in lysis buffer (20 mM Tris HCl pH 8, 137 mM NaCl, 10% glycerol, 1% NP40, 2 mM EDTA). 1mg of proteins was immunoprecipitated, utilizing 4 μg of PIN1, AR antibody or mouse IgG overnight at 4°C Extracts were incubated with antibodies and protein A/G beads (Pierce) for 3 h at 4°C.

[Page 65]

The remaining bacteria were then resuspended in NENT buffer plus 2% of N-lauryl-sarcosine, then pelleted and finally, the supernatants were collected again. The combined supernatants were incubated with glutathione agarose beads (Sigma Inc., St Louis, MO, USA) overnight at 4 oC. The agarose was then pelleted and washed three times in NENT buffer. The GST protein was analyzed by electrophoresis gel and blue coomassie staining. 1mg of protein was pulled-down with 10 ug of GST or GST-PIN1. To dephosphorylate proteins, 1mg of protein lysate was treated with 50 U of shrimp alkaline phosphatase for 1h at 37 oC.

Co-immunoprecipitation assay

Sub-confluent T98G cells were harvested and nuclear/cytoplasmatic proteins were prepared as follows: the cell pellet was resuspended in NP40 lysis

[Page 66]

buffer (0.01M Tris-HCl, 0.01M NaCl, 0.003M MgCl2, 0.03M Sucrose, 0.5% NP40) to prepare the cytoplasmatic fraction. Afterwards, nuclei were pelleted and resuspended in lysis buffer (20 mM Tris HCl pH 8, 137 mM NaCl, 10% glycerol, 1% NP40, 2 mM EDTA). 1mg of proteins was immunoprecipitated, utilizing 4 μg of PIN1 antibody.

Anmerkungen

Although nearly identical, nothing has been marked as a citation. Continued from previous page.

Sichter
(Graf Isolan), SleepyHollow02

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