CANCER Mdm2 Gets in the Akt

Abstract: Members of the Akt (also known as protein kinase B) family have been implicated in tumorigenesis ever since their discovery as a cellular gene coopted by a transforming retrovirus. Mayo and Donner have now clarified a molecular mechanism that likely contributes to control of cell growth and viability. They provide evidence that the protein Mdm2 is a target for phosphorylation by Akt in vitro and in vivo. Mdm2 functions to regulate the tumor suppressor protein p53. Mdm2 binds to p53 in the nucleus and inhibits transcriptional activation by p53, and also carries p53 out of the nucleus, where the E3 ubiquitin ligase activity of Mdm2 modifies p53 and targets it for degradation. All of this now appears to depend on the activity of Akt because phosphorylation of Mdm2 is required for translocation of Mdm2 from the cytoplasm to the nucleus, where it can contact p53. Testa and Bellacosa succinctly place the new results into context with other evidence for a central role of Akt in tumorigenesis.

L. D. Mayo, D. B. Donner. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl. Acad. Sci. U.S.A. 98, 11598-11603 (2001) [Abstract] [Full Text]

J. R. Testa, A. Bellacosa, AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A 98, 10983-10985 (2001). [Full Text]