title: Co-chaperon DnaJC7/TPR2 enhances p53 stability and activity through blocking the complex formation between p53 and MDM2.
abstract: 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.
authors.affiliation: Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kubo
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Yukari
authors.initials: Y
authors.lastname: Yoshihara
authors.forename: Meixiang
authors.initials: M
authors.lastname: Sang
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
mesh_terms: D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006207:Half-Life; D006360:Heat-Shock Proteins; D006801:Humans; D018832:Molecular Chaperones; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: C485782:DNAJC7 protein, human; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2