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Functional characterization of the ‘PBX interacting protein’ (HPIP) in normal and malignant human haematopoiesis.

von Dr. Pak

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[1.] Pak/Fragment 027 01 - Diskussion
Zuletzt bearbeitet: 2014-04-06 08:36:10 Hindemith
Abramovich et al 2000, BauernOpfer, Fragment, Gesichtet, Pak, SMWFragment, Schutzlevel sysop

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Hindemith
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Untersuchte Arbeit:
Seite: 27, Zeilen: 1-28
Quelle: Abramovich et al 2000
Seite(n): 26172, 26173, 26176, Zeilen: 26172: l.col: 1-4, 29-34 - r.col: 1-17, 40-47 - 26173: l.col: 1-3; 26176: r.col: 2-4
PBX1 is a homeodomain protein that functions in complexes with other homeodomain-containing proteins to regulate gene expression during development and/or differentiation processes. PBX is a member of the PBC protein family. The human PBX1 protein was initially identified as the chromosome 1 participant of the t(1;19) translocation, which occurs in 25 % of paediatric pre-B cell acute lymphocytic leukaemia which creates a chimeric gene designated E2A-PBX1.102

The mechanism by which E2A-PBX1 causes leukaemia is still unclear. However, the structure of the fusion protein, in which the majority of PBX1, including the homeodomain, is fused to the transcriptional activation domain of suggests that the oncogenic properties of E2A-PBX1 result from inappropriate regulation of target genes, of which the expression during haematopoiesis is normally regulated by wild-type PBX proteins.103,104 In vitro and in vivo data suggest that PBX functions in combination with heterologous homeodomain proteins, including class I HOX proteins. As HOX cofactors, PBC proteins improve HOX specificity due to the increased size of the cooperative binding site and the strength of DNA binding sites by different groups of HOX proteins.89,93

In addition, cooperative DNA binding with PBC proteins may act to change the regulatory signal of HOX proteins, from repressors to activators.78 PBX proteins appear to function as part of large nucleoprotein complexes. The interactions within these complexes are probably decisive factors that allow the DNA binding proteins to discriminate among target regulatory elements. How these complexes are regulated during either early embryonic development or cellular differentiation of somatic cells to control gene expression is still unclear. Abramovich et al. (2000) speculated that the characterization of additional PBX-interacting proteins might shed light on the mechanism of PBX function, and specifically sought to identify novel cofactors or modifiers of PBX1.105 Although the PBX homeodomain protein is thought to function as a transcription factor, its mechanism of action is still unknown.


78.Pineault N, Helgason CD, Lawrence HJ, Humphries RK. Differential expression of Hox, Meis1, and Pbx1 genes in primitive cells throughout murine hematopoietic ontogeny. Exp Hematol. 2002;30:49-57.

89.Mann RS, Chan SK. Extra specificity from extradenticle: the partnership between HOX and PBX/EXD homeodomain proteins. Trends Genet. 1996;12:258-262.

93.Shen WF, Montgomery JC, Rozenfeld S, et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol. 1997;17:6448-6458.

102.Kamps MP, Look AT, Baltimore D. The human t(1;19) translocation in pre-B ALL produces multiple nuclear E2A-Pbx1 fusion proteins with differing transforming potentials. Genes Dev. 1991;5:358-368.

103.Thorsteinsdottir U, Krosl J, Kroon E, Haman A, Hoang T, Sauvageau G. The oncoprotein E2APbx1a collaborates with Hoxa9 to acutely transform primary bone marrow cells. Mol Cell Biol. 1999;19:6355-6366.

104.LeBrun DP, Cleary ML. Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias. Oncogene. 1994;9:1641-1647.

105.Abramovich C, Shen WF, Pineault N, et al. Functional cloning and characterization of a novel nonhomeodomain protein that inhibits the binding of PBX1-HOX complexes to DNA. J Biol Chem. 2000;275:26172-26177.

PBX1 is a homeodomain protein that functions in complexes with other homeodomain-containing proteins to regulate gene expression during developmental and/or differentiation processes. [...]

[...] PBX1, a member of the PBX family along with PBX2 and PBX3 (4), was initially identified as the chromosome 1 participant of the t(1;19) translocation, which occurs in 25% of pediatric pre-B cell acute lymphocytic leukemia and that creates a chimeric gene designated E2A-PBX1 (5, 6). The mechanism by which E2A-PBX1 causes leukemia is still unclear. However, the structure of the protein, in which the majority of PBX1, including the homeodomain, is fused to the transcriptional activation domain of E2A (6, 7), suggests that the oncogenic properties of E2A-PBX1 result from inappropriate regulation of target genes whose expression during hematopoiesis is normally regulated by wild type PBX proteins (8–11).

In vitro and in vivo data strongly suggest that PBX functions in combination with heterologous homeodomain proteins, including class I HOX proteins. As HOX cofactors, PBC proteins improve HOX specificity due to the increased size of the cooperative binding site and the strength of DNA binding, as well as by modulating recognition of cooperative binding sites by different groups of HOX proteins (12–14). In addition, cooperative DNA binding with PBC proteins may act to change the regulatory signal of HOX proteins, from repressors to activators (15). [...]

[...]

PBX proteins thus appear to function as part of large nucleoprotein complexes. The interactions within these complexes are probably decisive factors that allow the DNA binding proteins to discriminate among target regulatory elements. How these complexes are regulated during either early embryonic development or cellular differentiation of somatic cells to control gene expression is still unclear. We speculated that characterization of additional PBX-interacting proteins might shed

[page 26173]

light on the mechanism of PBX function, and specifically, we sought to identify novel cofactors or modifiers of PBX1 using the yeast two-hybrid system.

[page 26176]

Although PBX homeodomain protein is thought to function as a transcription factor, its mechanism of action remains unknown.


4. Monica, K., Galili, N., Nourse, J., Saltman, D., and Cleary, M. L. (1991) Mol. Cell. Biol. 11, 6149–6157

5. Kamps, M. P., Look, A. T., and Baltimore, D. (1991) Genes Dev. 5, 358–368

6. Nourse, J., Mellentin, J. D., Galili, N., Wilkinson, J., Stanbridge, E., Smith S. D., and Cleary, M. L. (1990) Cell 60, 535–545

7. Kamps, M. P., Murre, C., Sun, X. H., and Baltimore, D. (1990) Cell 60, 547–555

8. LeBrun, D. P., and Cleary, M. L. (1994) Oncogene 9, 1641–1647

9. Lu, Q., Knoepfler, P. S., Scheele, J., Wright, D. D., and Kamps, M. P. (1995) Mol. Cell. Biol. 15, 3786–3795

10. Van Dijk, M. A., Voorhoeve, P. M., and Murre, C. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 6061–6065

11. Thorsteinsdottir, U., Krosl, J., Kroon, E., Haman, A., Hoang, T., and Sauvageau, G. (1999) Mol. Cell. Biol. 19, 6355–6366

12. Mann, R. S., and Chan, S. K. (1996) Trends Genet. 12, 258–262

13. Shen, W. F., Chang, C. P., Rozenfeld, S., Sauvageau, G., Humphries, R. K., Lu, M., Lawrence, H. J., Cleary, M. L., and Largman, C. (1996) Nucleic Acids Res. 24, 898–906

14. Shen, W. F., Rozenfeld, S., Lawrence, H. J., and Largman, C. (1997) J. Biol. Chem. 272, 8198–8206

15. Pinsonneault, J., Florence, B., Vaessin, H., and McGinnis, W. (1997) EMBO J. 16, 2032–2042

Anmerkungen

The source is given, but only for few line towards the end of the passage.

Note that also most of the references are parallel in the thesis and the source.

Sichter
(Hindemith) Schumann


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