title: DNAJB1 stabilizes MDM2 and contributes to cancer cell proliferation in a p53-dependent manner.
abstract: Both MDM2 and MDMX regulate p53, but these proteins play different roles in this process. To clarify the difference, we performed a yeast 2 hybrid (Y2H) screen using the MDM2 acidic domain as bait. DNAJB1 was found to specifically bind to MDM2, but not MDMX, in vitro and in vivo. Further investigation revealed that DNAJB1 stabilizes MDM2 at the post-translational level. The C-terminus of DNAJB1 is essential for its interaction with MDM2 and for MDM2 accumulation. MDM2 was degraded faster by a ubiquitin-mediated pathway when DNAJB1 was depleted. DNAJB1 inhibited the MDM2-mediated ubiquitination and degradation of p53 and contributed to p53 activation in cancer cells. Depletion of DNAJB1 in cancer cells inhibited activity of the p53 pathway, enhanced the activity of the Rb/E2F pathway, and promoted cancer cell growth in vitro and in vivo. This function was p53 dependent, and either human papillomavirus (HPV) E6 protein or siRNA against p53 was able to block the contribution caused by DNAJB1 depletion. In this study, we discovered a new MDM2 interacting protein, DNAJB1, and provided evidence to support its p53-dependent tumor suppressor function.
authors.affiliation: Department of Plastic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Qi
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
authors.forename: Jianglin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China. Electronic address: weiqizeng@gmail.com.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zeng
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, PR China. Electronic address: chenxiangck@gmail.com.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015723:Gene Library; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; C494647:DNAJB1 protein, human; C052603:E6 protein, Human papillomavirus type 18; D050956:HSP40 Heat-Shock Proteins; D009856:Oncogene Proteins, Viral; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: DNAJB1; HSP70; MDM2; p21; p53