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Loss of LZAP inactivates p53 and regulates sensitivity of cells to DNA damage in
a p53-dependent manner
#MMPMID28394357
Wamsley JJ
; Gary C
; Biktasova A
; Hajek M
; Bellinger G
; Virk R
; Issaeva N
; Yarbrough WG
Oncogenesis
2017[Apr]; 6
(4
): e314
PMID28394357
show ga
Chemotherapy and radiation, the two most common cancer therapies, exert their
anticancer effects by causing damage to cellular DNA. However, systemic treatment
damages DNA not only in cancer, but also in healthy cells, resulting in the
progression of serious side effects and limiting efficacy of the treatment.
Interestingly, in response to DNA damage, p53 seems to play an opposite role in
normal and in the majority of cancer cells-wild-type p53 mediates apoptosis in
healthy tissues, attributing to the side effects, whereas mutant p53 often is
responsible for acquired cancer resistance to the treatment. Here, we show that
leucine zipper-containing ARF-binding protein (LZAP) binds and stabilizes p53.
LZAP depletion eliminates p53 protein independently of its mutation status,
subsequently protecting wild-type p53 cells from DNA damage-induced cell death,
while rendering cells expressing mutant p53 more sensitive to the treatment. In
human non-small-cell lung cancer, LZAP levels correlated with p53 levels,
suggesting that loss of LZAP may represent a novel mechanism of p53 inactivation
in human cancer. Our studies establish LZAP as a p53 regulator and p53-dependent
determinative of cell fate in response to DNA damaging treatment.
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