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2016 ; 2
(ä): 16039
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A novel mutant p53 binding partner BAG5 stabilizes mutant p53 and promotes mutant
p53 GOFs in tumorigenesis
#MMPMID27807478
Yue X
; Zhao Y
; Huang G
; Li J
; Zhu J
; Feng Z
; Hu W
Cell Discov
2016[]; 2
(ä): 16039
PMID27807478
show ga
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.