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

Rosario Amato1, Lucia D'Antona, Giovanni Porciatti

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

Journal of Molecular Medicine (Berlin, Germany)
|September 17, 2009
PubMed

Insights

Serum and glucocorticoid regulated kinase 1 (Sgk1) enhances p53 ubiquitylation, promoting cell survival and cancer chemotherapy resistance. This kinase activity, regulated by p53, suggests a feedback loop influencing tumor progression.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Background:

  • Serum and glucocorticoid regulated kinase 1 (Sgk1) is a key kinase involved in cell survival and steroid signaling.
  • Sgk1 activation is linked to growth factor signaling and may contribute to cancer chemotherapy resistance.
  • The interplay between Sgk1 and the tumor suppressor p53 is not fully understood.

Purpose of the Study:

  • To investigate the role of Sgk1 in p53 ubiquitylation and its downstream effects.
  • To elucidate the functional relationship between Sgk1 and p53 in cancer cells.
  • To propose a regulatory model for Sgk1 and p53 interaction.

Main Methods:

  • Sgk1-specific RNA silencing in RKO and other cell lines.
  • Experiments in a mouse model and transfected HeLa cells (wild-type and dominant-negative Sgk1).
  • Analysis of p53 ubiquitylation, cell survival, cell-cycle progression, and clonogenic potential.

Main Results:

  • Sgk1 was demonstrated to activate MDM2-dependent p53 ubiquitylation.
  • Sgk1 influences cell survival, cell-cycle progression, and epithelial de-differentiation.
  • The impact of Sgk1 on cancer cell clonogenic potential is dependent on wild-type p53 expression.
  • A feedback loop was proposed where Sgk1 down-regulates p53 via ubiquitylation.

Conclusions:

  • Sgk1 plays a critical role in regulating p53 stability and function through ubiquitylation.
  • Sgk1 contributes to cancer cell survival and proliferation, with effects modulated by p53 status.
  • The findings suggest a novel feedback mechanism involving Sgk1 and p53 with implications for cancer therapy.

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