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Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation.
- Source :
-
Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2009 Dec; Vol. 87 (12), pp. 1221-39. Date of Electronic Publication: 2009 Sep 11. - Publication Year :
- 2009
-
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.
- Subjects :
- Animals
Cell Death
Cell Line
HeLa Cells
Humans
Male
Mice
Mice, Inbred BALB C
Mice, Transgenic
Signal Transduction
Transfection
Cell Differentiation
Cell Proliferation
Cell Survival
Gene Expression Regulation, Neoplastic
Immediate-Early Proteins genetics
Immediate-Early Proteins metabolism
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-mdm2 genetics
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1432-1440
- Volume :
- 87
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of molecular medicine (Berlin, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 19756449
- Full Text :
- https://doi.org/10.1007/s00109-009-0525-5