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

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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.

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Acknowledgments

We thank the American Journal Experts for the editorial revision of the manuscript. This work was supported by the Fondazione Carical, Cofin 2005/068017_004, Interlink II04C0G4EM, Cofin 2006/prot. 2006065339_005, and Firb 2001/RBNE01724C_007. Rosario Amato was partially supported by the Fondazione “Lilli Funaro”.

Conflict of interest statement

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Experimental and clinical Medicine “G. Salvatore”, Faculty of Medicine, University Magna Graecia at Catanzaro, Catanzaro, Italy

    Rosario Amato, Lucia D’Antona, Giovanni Porciatti, Valter Agosti, Miranda Menniti, Giorgio Fuiano & Nicola Perrotti

  2. Department of Pharmacobiology, University “Magna Graecia” Catanzaro, Catanzaro, Italy

    Nicola Costa

  3. CSS-Mendel Institute, Rome, Italy

    Emanuele Bellacchio

  4. Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome, Italy

    Cinzia Rinaldo & Silvia Soddu

  5. Department for the Development of Therapeutic Programs, Regina Elena Cancer Institute, Rome, Italy

    Emanuele Bellacchio, Stefano Mattarocci & Marco G. Paggi

  6. Department of Physiology, University of Tübingen, Tübingen, Germany

    Florian Lang

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  1. Rosario Amato
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  2. Lucia D’Antona
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  3. Giovanni Porciatti
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Correspondence to Nicola Perrotti.

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Amato, R., D’Antona, L., Porciatti, G. et al. Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation. J Mol Med 87, 1221–1239 (2009). https://doi.org/10.1007/s00109-009-0525-5

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  • DOI: https://doi.org/10.1007/s00109-009-0525-5

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