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Nierenfunktion Kinase-defizienter Mäuse

von Dr. Diana Sandulache

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[1.] Dsa/Fragment 031 01 - Diskussion
Zuletzt bearbeitet: 2016-08-09 20:47:22 WiseWoman
Dsa, Fragment, Gesichtet, KomplettPlagiat, Lang et al 2006, SMWFragment, Schutzlevel sysop

Typus
KomplettPlagiat
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 31, Zeilen: 1-32
Quelle: Lang et al 2006
Seite(n): 1151: 1152, 1155, Zeilen: 1151: abstract; 1152: r.col: 5ff; 1155: l.col: 3ff
1.7. Degradation of SGKs

SGK1 is rapidly degraded, with a half-life of 30 min (Brickley DR. et al., (2002) J Biol Chem). Ubiquitination of SGK1 labels the kinase for degradation by the proteasome (Brickley DR. et al., (2002) J Biol Chem). SGK1 degradation may be mediated by the ubiquitin ligase Nedd4–2 (neuronal precursor cells expressed developmentally downregulated) (Zhou R.et al., (2005) Biol Chem). Nedd4–2 contains a series of tryptophan-rich sequences (WW motifs) that interact with a proline-tyrosine PY motif present in its target proteins. SGK1 bears such a PY motif. Overexpression of Nedd4–2 decreases steady state levels of SGK1 in a dose-dependent manner by increasing SGK1 ubiquitination (presumably within the first 60 NH2-terminal amino acids) and subsequent degradation in the 26S proteasome. Conversely, silencing of Nedd4–2 by RNA interference, or loss of the NH2-terminal amino acids, abrogates the ubiquitination and thus increases the half-life of SGK1. The effect of Nedd4–2 apparently requires phosphorylation of the ubiquitin ligase by SGK1, as SGK1 degradation is reduced by a phosphorylation site-deficient Nedd4–2 mutant (Nedd4–2S/T-A) or by SGK1 inhibition. Accordingly, active SGK1 favors its own degradation, thus contributing to the limitation of its action (Zhou R. et al., (2005) J Biol Chem).

1.8. Influence of SGK on renal function

SGKs activate ion channels (e.g. ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g. NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g. glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g. forkhead transcription factor FKHRL1). The functional significance of SGK1, SGK2, and SGK3 is still far from understood. Notably, all three kinases are potent regulators of ion channel activity, transport, and transcription (Bhargava A. and Pearce D., (2004) Trends Endocrinol Metab; Fillon S. et al., (2001) Comp Biochemi Physiol Mol Integr Physiol). Functional analysis of gene-targeted mice lacking SGK1 (Wulff P. et al., (2002) J Clin Invest) and SGK3 (McCormick JA. et al., (2004) Moll Biol Cell) provided insight into the functional significance of SGK1- and SGK3-dependent regulation of physiological functions. Interestingly, neither knockout of SGK1 or SGK3, nor knockout of both SGK1 and SGK3 leads to a severe phenotype, suggesting that neither SGK1 nor SGK3 is required for survival. Closer inspection of the renal physiology of those mice discloses, however, multiple physiological deficits pointing to the broad functional role of these kinases.

SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, β-catenin, nuclear factor κB).


[page 1152]

The functional significance of SGK1, SGK2, and SGK3 is still far from understood. Notably, all three kinases are potent regulators of ion channel activity, transport, and transcription (30, 111, 183, 186, 250, 305, 331, 378). Functional analysis of gene-targeted mice lacking SGK1 (368) and SGK3 (214) provided insight into the functional significance of SGK1- and SGK3-dependent regulation of physiological functions. Interestingly, neither knockout of SGK1 (368) or SGK3 (214), nor knockout of both SGK1 and SGK3 (133) leads to a severe phenotype, suggesting that neither SGK1 nor SGK3 is required for survival. Closer inspection of the physiology of those mice discloses, however, multiple physiological deficits pointing to the broad functional role of these kinases.

[page 1155]

C. Degradation of SGKs

SGK1 is rapidly degraded, with a half-life of 30 min (50). Ubiquitination of SGK1 labels the kinase for degradation by the proteasome (50). SGK1 degradation may be mediated by the ubiquitin ligase Nedd4–2 (neuronal precursor cells expressed developmentally downregulated) (386). Nedd4–2 contains a series of tryptophan-rich sequences (WW motifs) that interact with a proline-tyrosine PY motif present in its target proteins. SGK1 bears such a PY motif. Overexpression of Nedd4–2 decreases steady-state levels of SGK1 in a dose-dependent manner by increasing SGK1 ubiquitination (presumably within the first 60 NH2-terminal amino acids) and subsequent degradation in the 26S proteasome. Conversely, silencing of Nedd4–2 by RNA interference, or loss of the NH2-terminal amino acids, abrogates the ubiquitination and thus increases the half-life of SGK1. The effect of Nedd4–2 apparently requires phosphorylation of the ubiquitin ligase by SGK1, as SGK1 degradation is reduced by a phosphorylation site-deficient Nedd4–2 mutant (Nedd4–2S/T-A) or by SGK1 inhibition (Fig. 1). Accordingly, active SGK1 favors its own degradation, thus contributing to the limitation of its action (386).


30. Bhargava A and Pearce D. Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene products. Trends Endocrinol Metab 15: 147–153, 2004.

50. Brickley DR, Mikosz CA, Hagan CR, and Conzen SD. Ubiquitin modification of serum and glucocorticoid-induced protein kinase-1 (SGK-1). J Biol Chem 277: 43064–43070, 2002.

111. Fillon S, Warntges S, Matskevitch J, Moschen I, Setiawan I, Gamper N, Feng YX, Stegen C, Friedrich B, Waldegger S, Broer S, Wagner CA, Huber SM, Klingel K, Vereninov A, and Lang F. Serum- and glucocorticoid-dependent kinase, cell volume, and the regulation of epithelial transport. Comp Biochem Physiol A Mol Integr Physiol 130: 367–376, 2001.

133. Grahammer F, Henke G, Sandu C, Rexhepaj R, Hussain A, Friedrich B, Risler T, Just L, Skutella T, Wulff P, Kuhl D, and Lang F. Intestinal function of gene targeted mice lacking the serum and glucocorticoid inducible kinase SGK1. Am J Physiol Gastrointest Liver Physiol 290: G1114–G1123, 2006.

183. Lang F, Henke G, Embark HM, Waldegger S, Palmada M, Bohmer C, and Vallon V. Regulation of channels by the serum and glucocorticoid-inducible kinase: implications for transport, excitability and cell proliferation. Cell Physiol Biochem 13: 41–50, 2003.

186. Lang F, Vallon V, Grahammer F, Palmada M, and Bohmer C. Transport regulation by the serum- and glucocorticoid-inducible kinase SGK1. Biochem Soc Trans 33: 213–215, 2005.

214. McCormick JA, Feng Y, Dawson K, Behne MJ, Yu B, Wang J, Wyatt AW, Henke G, Grahammer F, Mauro TM, Lang F, and Pearce D. Targeted disruption of the protein kinase SGK3/CISK impairs postnatal hair follicle development. Mol Biol Cell 15: 4278– 4288, 2004.

250. Pearce D. SGK1 regulation of epithelial sodium transport. Cell Physiol Biochem 13: 13–20, 2003.

305. Stockand JD. New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol 282: F559–F576, 2002.

331. Verrey F, Loffing J, Zecevic M, Heitzmann D, and Staub O. SGK1: aldosterone-induced relay of Na+ transport regulation in distal kidney nephron cells. Cell Physiol Biochem 13: 21–28, 2003.

368. Wulff P, Vallon V, Huang DY, Volkl H, Yu F, Richter K, Jansen M, Schlunz M, Klingel K, Loffing J, Kauselmann G, Bosl MR, Lang F, and Kuhl D. Impaired renal Na+ retention in the sgk1-knockout mouse. J Clin Invest 110: 1263–1268, 2002.

378. Yun CC. Concerted roles of SGK1 and the Na+/H+ exchanger regulatory factor 2 (NHERF2) in regulation of NHE3. Cell Physiol Biochem 13: 029–040, 2003.

386. Zhou R and Snyder PM. Nedd4–2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem 280: 4518–4523, 2005.

Anmerkungen

The source is not given.

Sichter
(Hindemith), WiseWoman

[2.] Dsa/Fragment 031 34 - Diskussion
Zuletzt bearbeitet: 2016-08-03 20:12:44 WiseWoman
Boini 2006, Dsa, Fragment, Gesichtet, KomplettPlagiat, SMWFragment, Schutzlevel sysop

Typus
KomplettPlagiat
Bearbeiter
Hindemith
Gesichtet
Yes.png
Untersuchte Arbeit:
Seite: 31, Zeilen: 34-42
Quelle: Boini 2006
Seite(n): 15, Zeilen: 8ff
a) Role of SGK1 in aldosterone dependent Na+ reabsorption

Although SGK isoforms are expressed in various tissues and cell types, the role of SGK1 in aldosterone-dependent regulation of Na+ homeostasis is the best-studied function of these kinases with respect to epithelial ion transport. The kidneys play a pivotal role in the maintenance of Na+ homeostasis. Urinary Na+ excretion must be tightly regulated to maintain a constant extracellular volume during varying dietary Na+ intake and extrarenal Na+ losses. The final control of renal Na+ excretion is achieved by the ASDN i.e. the late distal convoluted tubule, the connecting tubule and the cortical as well as the medullary collecting ducts (CCD and MCD respectively) (Loffing J. et al., (2001) Am J Physiol Renal Physiol).

1.5 Role of SGK1 in Aldosterone Dependent Na+ Reabsorption

Although SGK isoforms are expressed in various tissues and cell types, the role of SGK1 in aldosterone-dependent regulation of Na+ homeostasis is the best-studied function of these kinases with respect to epithelial ion transport. The kidneys play a pivotal role in the maintenance of Na+ homeostasis. Urinary Na+ excretion must be tightly regulated to maintain a constant extracellular volume during varying dietary Na+ intake and extrarenal Na+ losses. The final control of renal Na+ excretion is achieved by the ASDN i.e. the late distal convoluted tubule, the connecting tubule, and the cortical as well as the medullary collecting ducts (CCD and MCD respectively) (Loffing et al., 2001).

Anmerkungen

The source is not given.

Sichter
(Hindemith), WiseWoman


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