Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation

Abstract

Serum and glucocorticoid regulated kinase 1 (Sgk1) is a serine-threonine kinase that is activated by serum, steroids, insulin, vasopressin, and interleukin 2 at the transcriptional and post-translational levels. Sgk1 is also important in transduction of growth factors and steroid-dependent survival signals and may have a role in the development of resistance to cancer chemotherapy. In the present paper, we demonstrate that Sgk1 activates MDM2-dependent p53 ubiquitylation. The results were obtained in RKO cells and other cell lines by Sgk1-specific RNA silencing and were corroborated in an original mouse model as well as in transiently and in stably transfected HeLa cells expressing wild-type or dominant negative Sgk1 mutant. Sgk1 contributes to cell survival, cell-cycle progression, and epithelial de-differentiation. We also show that the effects of Sgk1 on the clonogenic potential of different cancer cells depend on the expression of wild-type p53. Since transcription of Sgk1 is activated by p53, we propose a finely tuned feedback model where Sgk1 down-regulates the expression of p53 by enhancing its mono- and polyubiquitylation.

mTOR-Dependent Cell Survival Mechanisms

“…It is reported that SGK can regulate cell viability through activation of MDM2-dependent p53 degradation (Amato et al 2009). Moreover, like AKT, SGK also exists in three isoforms (SGK1, SGK2, and SGK3) in human and mouse (Brunet et al 2001).…”

Chronic restraint stress attenuates p53 function and promotes tumorigenesis

“…SGK1 shares high sequence homology with AKT (∼50% through their catalytic domain) and a similar consensus phosphorylation site RXRXXS/ T with AKT (17), which negatively regulates p53 function through the activation of MDM2. A recent study reported that SGK1 negatively regulates p53 in several human cancer cell lines through the activation of MDM2 (18). This raises the possibility that the induction of SGK1 under chronic restraint may mediate the effect of glucocorticoids on p53.…”

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

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Conflict of interest:The authors have declared that no conflict of interest exists.Nonstandard abbreviations used: SGK1, serum-and glucocorticoid-inducible kinase 1; RPL, recurrent pregnancy loss; ENaC, epithelial sodium channel; HESC, human endometrial stromal cells; ROS, reactive oxygen species; IVF, in vitro fertilization; dpc, days post coitus.

2Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations 1,2 .Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus.

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“…Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus.…”

“…SGK1 is a key regulator of sodium transport in mammalian epithelia, most prominently through its ability to directly activate epithelial sodium channel (ENaC) and to enhance their expression by inhibiting the ubiquitin ligase NEDD4-2 5,6 . SGK1 is also involved in proliferation and cell survival responses 3,4 . To determine if SGK1 regulates embryo implantation, we first examined its expression in midsecretory endometrial samples from women with proven fertility and from subjects with either unexplained infertility or a history of RPL, defined here as 3 or more consecutive miscarriages (Supplementary Table 1).…”