Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2

• Published in: Biochemical and biophysical research communications 2013-01, Vol.430 (3), p.1034-1039
• Main Authors: Kubo, Natsumi, Wu, Dan, Yoshihara, Yukari, Sang, Meixiang, Nakagawara, Akira, Ozaki, Toshinori
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Cercopithecus aethiops; COS Cells; DnaJC7; Half-Life; HSP40 Heat-Shock Proteins - metabolism; Humans; MDM2; p53; Protein Stability; Proto-Oncogene Proteins c-mdm2 - metabolism; TPR2; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Two-hybrid; Two-Hybrid System Techniques
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2012.11.121

► DnaJC7 is associated with DNA-binding domain of p53. ► DnaJC7 enhances transcriptional and growth-suppressive activities of p53. ► DnaJC7 stabilizes p53 by inhibiting complex formation between p53 and MDM2. Tumor suppressor p53 plays a critical role in the regulation of DNA damage response. Upon severe DNA damage, p53 promotes apoptosis to eliminate cells with seriously damaged DNA to maintain genomic integrity. Pro-apoptotic function of p53 is tightly linked to its sequence-specific transactivation ability. In the present study, we have identified co-chaperon DnaJC7/TPR2 as a novel binding partner of p53 by yeast-based two-hybrid screening. In the two-hybrid screening, we used the central DNA-binding domain of p53 as a bait. Co-immunoprecipitation experiments demonstrated that DnaJC7 is associated with p53 in mammalian cells. Luciferase reporter and colony formation assays revealed that DnaJC7 enhances p53-dependent transcriptional as well as growth-suppressive activity. Forced expression of DnaJC7 induced to extend a half-life of p53, indicating that DnaJC7-mediated activation of p53 might be at least in part due to its prolonged half-life. Consistent with these observations, the amount of p53/MDM2 complex was markedly reduced in the presence of DnaJC7, suggesting that DnaJC7 dissociates MDM2 from p53. Taken together, our present findings strongly suggest that DnaJC7 participates in p53/MDM2 negative feedback regulatory pathway, and thereby enhancing the stability and activity of p53.