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Signaling and Regulation

G_12/13 Basally Regulates p53 through Mdm4 Expression

¹ College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University; ² College of Pharmacy, Duksung Women's University; and ³ Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea

Requests for reprints: Sang Geon Kim, College of Pharmacy, Seoul National University, Sillim-dong, Kwanak-Gu, Seoul 151-742, Korea. Phone: 82-2880-7840; Fax: 82-2872-1795. E-mail: sgk{at}snu.ac.kr

G_12/13, which belongs to the G₁₂ family, participates in the regulation of diverse physiologic processes. In view of the control of G_12/13 in cell proliferation, this study investigated the role of G_12/13 in the regulation of p53 and mdm4. Immunoblotting and immunocytochemistry revealed that p53 was expressed in control embryonic fibroblasts and was largely localized in the nuclei. G₁₂ deficiency decreased p53 levels and its DNA binding activity, accompanying p21 repression with Bcl₂ induction, whereas G₁₃ deficiency exerted weak effects. G₁₂ or G₁₃ deficiency did not change p53 mRNA expression. ERK1/2 or Akt was not responsible for p53 repression due to G₁₂ deficiency. Mdm4, a p53-stabilizing protein, was repressed by G₁₂ deficiency and to a lesser extent by G₁₃ deficiency, whereas mdm2, PTEN, ß-catenin, ATM, and Chk2 were unaffected. p53 accumulation by proteasomal inhibition during G₁₂ deficiency suggested the role of G₁₂ in p53 stabilization. Constitutively active G₁₂ (G₁₂QL) or G₁₃ (G₁₃QL) promoted p53 accumulation with mdm4 induction in MCF10A cells. p53 accumulation by mdm4 overexpression, but no mdm4 induction by p53 overexpression, and small interfering RNA knockdown verified the regulatory role of mdm4 for p53 downstream of G_12/13. In control or G₁₂/G₁₃-deficient cells, genotoxic stress led to p53 accumulation. At concentrations increasing the flow cytometric pre-G₁ phase, doxorubicin or etoposide treatment caused serine phosphorylations in G₁₂–/– or G_12/13–/– cells, but did not induce mdm4. G_12/13QL transfection failed to phosphorylate p53 at serines. Our results indicate that G_12/13 regulate basal p53 levels via mdm4, which constitutes a cell signaling pathway distinct from p53 phosphorylations elicited by genotoxic stress. (Mol Cancer Res 2007;5(5):473–84)

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