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Akt Phosphorylates and Regulates Pdcd4 Tumor Suppressor Protein

Comprehensive Cancer Center, Human Cancer Genetics Program, and Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University School of Medicine, Ohio State University, Columbus, Ohio

Requests for reprints: Yuri Pekarsky, Comprehensive Cancer Center, Ohio State University, 435 Wiseman Hall, 410 West 12th Avenue, Columbus, OH 43210. Phone: 614-292-3120; Fax: 614-292-3312. E-mail: Pekarsky.Yuri{at}osumc.edu.

Programmed cell death 4 (Pdcd4) is a tumor suppressor protein that interacts with eukaryotic initiation factor 4A and inhibits protein synthesis. Pdcd4 also suppresses the transactivation of activator protein-1 (AP-1)–responsive promoters by c-Jun. The Akt (protein kinase B) serine/threonine kinase is a key mediator of phosphoinositide 3-kinase pathway involved in the regulation of cell proliferation, survival, and growth. Because Pdcd4 has two putative Akt phosphorylation sites at Ser⁶⁷ and Ser⁴⁵⁷, we investigated whether Akt phosphorylates and regulates Pdcd4. Our results show that Akt specifically phosphorylates Ser⁶⁷ and Ser⁴⁵⁷ residues of Pdcd4 in vitro and in vivo. We further show that phosphorylation of Pdcd4 by Akt causes nuclear translocation of Pdcd4. Using luciferase assay, we show that phosphorylation of Pdcd4 by Akt also causes a significant decrease of the ability of Pdcd4 to interfere with the transactivation of AP-1–responsive promoter by c-Jun. (Cancer Res 2005; 65(24): 11282-6)

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