A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant p53 GOFs in tumorigenesis.

Xuetian Yue,Yuhan Zhao,Zhaohui Feng,Jun Li,Wenwei Hu,Grace Huang,Junlan Zhu

doi:10.1038/celldisc.2016.39

Xuetian Yue, Yuhan Zhao + Show 5 more

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https://doi.org/10.1038/celldisc.2016.39

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Abstract

Tumor suppressor p53 is the most frequently mutated gene in human tumors. Many tumor-associated mutant p53 (mutp53) proteins gain new tumor-promoting activities, including increased proliferation, metastasis and chemoresistance of tumor cells, which are defined as gain-of-functions (GOFs). Mutp53 proteins often accumulate at high levels in human tumors, which is important for mutp53 to exert their GOFs. The mechanism underlying mutp53 proteins accumulation in tumors is not fully understood. Here, we report that BAG5, a member of Bcl-2-associated athanogene (BAG) family proteins, promotes mutp53 accumulation in tumors, which in turn enhances mutp53 GOFs. Mechanistically, BAG5 interacts with mutp53 proteins to protect mutp53 from ubiquitination and degradation by E3 ubiquitin ligases MDM2 and CHIP, which in turn promotes mutp53 protein accumulation and therefore GOFs in promoting cell proliferation, tumor growth, cell migration and chemoresistance. BAG5 is frequently overexpressed in many human tumors and the overexpression of BAG5 is associated with poor prognosis of cancer patients. Altogether, this study revealed that inhibition of mutp53 degradation by BAG5 is a novel and critical mechanism underlying mutp53 protein accumulation and GOFs in cancer. Furthermore, our results also uncovered that promoting mutp53 accumulation and GOFs is a novel mechanism of BAG5 in tumorigenesis.

Highlights

Tumor suppressor p53 exerts its tumor suppressive function through regulation of a variety of biological processes, including cell cycle arrest, DNA repair, apoptosis, senescence, angiogenesis, metastasis, energy metabolism and response to chemotherapy [1, 2]
In our recent study, using IP combined with LC–MS/MS assays to pull-down mutp53 proteinbinding partners in tumors from mutp53 R172H knock-in mice, we found that BAG5 is a mutp53-binding protein (Table 1) [14]
We investigated whether BAG5 interacts with mutp53 protein in human cancer cells. p53-null human lung cancer H1299 cells were transfected with the expression vector of BAG5-Flag together with wtp53 or mutp53 (R175H)

Summary

Introduction

Tumor suppressor p53 exerts its tumor suppressive function through regulation of a variety of biological processes, including cell cycle arrest, DNA repair, apoptosis, senescence, angiogenesis, metastasis, energy metabolism and response to chemotherapy [1, 2]. The BAG2–mutp interaction blocks MDM2 from binding to and ubiquitinating mutp, which in turn promotes mutp accumulation and GOF in tumorigenesis [14]. Findings from this study revealed an important mechanism for mutp accumulation in tumors, it raised an interesting question: whether additional proteins containing BAG domain, especially those in the BAG family, have a similar function to interact with mutp protein and promote mutp accumulation and GOF in tumorigenesis? BAG5–mutp interaction inhibited the ubiquitination and degradation of mutp protein mediated by MDM2 and CHIP, which in turn stabilized mutp protein and promoted mutp GOFs in cell proliferation, tumor growth, metastasis and chemoresistance. Cell Discovery | www.nature.com/celldisc mechanism for mutp accumulation in tumors and an unidentified and critical role of BAG5 in tumorigenesis

Results

Discussion

Materials and Methods