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2016 ; 7
(16
): 22508-22
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English Wikipedia
Cancer-associated S100P protein binds and inactivates p53, permits
therapy-induced senescence and supports chemoresistance
#MMPMID26967060
Gibadulinova A
; Pastorek M
; Filipcik P
; Radvak P
; Csaderova L
; Vojtesek B
; Pastorekova S
Oncotarget
2016[Apr]; 7
(16
): 22508-22
PMID26967060
show ga
S100P belongs to the S100 family of calcium-binding proteins regulating diverse
cellular processes. Certain S100 family members (S100A4 and S100B) are associated
with cancer and used as biomarkers of metastatic phenotype. Also S100P is
abnormally expressed in tumors and implicated in migration-invasion, survival,
and response to therapy. Here we show that S100P binds the tumor suppressor
protein p53 as well as its negative regulator HDM2, and that this interaction
perturbs the p53-HDM2 binding and increases the p53 level. Paradoxically, the
S100P-induced p53 is unable to activate its transcriptional targets hdm2, p21WAF,
and bax following the DNA damage. This appears to be related to reduced
phosphorylation of serine residues in both N-terminal and C-terminal regions of
the p53 molecule. Furthermore, the S100P expression results in lower levels of
pro-apoptotic proteins, in reduced cell death response to cytotoxic treatments,
followed by stimulation of therapy-induced senescence and increased clonogenic
survival. Conversely, the S100P silencing suppresses the ability of cancer cells
to survive the DNA damage and form colonies. Thus, we propose that the oncogenic
role of S100P involves binding and inactivation of p53, which leads to aberrant
DNA damage responses linked with senescence and escape to proliferation. Thereby,
the S100P protein may contribute to the outgrowth of aggressive tumor cells
resistant to cytotoxic therapy and promote cancer progression.