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

Rosario Amato, Lucia D'Antona, Giovanni Porciatti, Valter Agosti, Miranda Menniti, Cinzia Rinaldo, Nicola Costa, Emanuele Bellacchio, Stefano Mattarocci, Giorgio Fuiano, Silvia Soddu, Marco G. Paggi, Florian Lang, Nicola Perrotti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1221-1239
Number of pages19
JournalJournal of Molecular Medicine
Volume87
Issue number12
DOIs
Publication statusPublished - Dec 2009

Keywords

  • Cell death
  • Cell signaling
  • MDM2
  • P53
  • Sgk1

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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