Wild-type p53-induced
phosphatase 1 (Wip1, PPM1D) is induced by p53 in response to various stressors and dephosphorylates cellular target
proteins involved in DNA repair and cell cycle checkpoint pathways. The Wip1 gene is frequently amplified or overexpressed in human
cancers, promoting
tumor growth by switching off major checkpoint
kinases and p53. To explore wild-type p53-independent Wip1 induction, Wip1 promoter activity and its transcript level were evaluated by
luciferase assay and real-time PCR, after
methylmethane sulfonate (MMS) treatment in
breast cancer cell lines and p53-null cell lines. Wip1 promoter activities in response to UV irradiation and various anti-
cancer agents were compared between wild-type and a p53-response
element (p53RE) mutated construct. Wip1 expression and its effects were examined in primary
non-small cell lung cancer (NSCLC) and colon
tumor cells by using Wip1-specific
siRNA. MMS induced Wip1 promoter activity in Hs578T, MDA-MB-231, and SK-BR-3 cells expressing
DNA binding-deficient p53 mutants. A549-E6 and HCT116 (p53(-/-)) cells retained substantial Wip1 induction. Wip1 promoter activity was reduced, but not eliminated, in cells expressing a promoter containing a mutated p53-response
element. Wip1 induction was not blocked by
SB202190 or
SP600125. MMS increased Wip1 expression in primary
non-small cell lung cancer cells expressing a p53 R175H mutant. Our data indicate that Wip1 is induced in the absence of functional p53, like
p38 MAPK and JNK, as a stress response terminator.