The estrogen receptor alpha pathway induces oncogenic Wip1 phosphatase gene expression.
Wild-type p53-induced phosphatase (Wip1) is a serine/threonine phosphatase induced by DNA-damaging agents. This enzyme dephosphorylates several cell cycle regulating proteins, including p53, p38 mitogen-activated protein kinase, Chk1, and Chk2, resulting in negative feedback regulation of p38-p53 signaling after damage repair. Moreover, the Wip1 gene may be amplified or overexpressed, especially in hormone-regulated organs, and Wip1 gene amplification has been correlated with poor prognosis in hormone-related malignancies, including ovarian cancers. We therefore investigated the link between estrogen signaling and Wip1 expression. We identified seven putative estrogen response elements within 3 kb of the Wip1 promoter. We also found that estradiol (E(2)) treatment produced a 3-fold increase in endogenous Wip1 mRNA and protein expression in MCF7 cells. Direct binding of estrogen receptor (ER)alpha to the Wip1 promoter after E(2) treatment was confirmed by a chromatin immunoprecipitation assay using ERalpha antibody and an electrophoretic mobility shift assay. Wip1 overexpression induced by adenovirus and E(2) facilitated the proliferation of serum-starved ZR-75-1 cells, with cell proliferation induced by overexpressed Wip1 approximately 25% higher than that induced by E(2). Wip1 phosphatase activity was essential for cell cycle progression. Wip1 stimulated the transcriptional activity of its own promoter through E(2)-ERalpha signaling. In addition, Wip1 overexpression induced Rb phosphorylation during cancer cell proliferation. These results indicate that Wip1 up-regulation is important in the pathogenesis of p53(+) and ER(+) breast cancer through the inactivation of p53 by dephosphorylation and the amplification of subsequent estrogenic effects through the E(2)-ERalpha-Wip1 pathway.
Department of Pathology, University of Ulsan College of Medicine, 388-1 Pungnap-2 dong, Songpa-gu, Seoul 138-736, Republic of Korea.
Hye-Sook
HS
Han
Eunsil
E
Yu
Ji-Young
JY
Song
Ji-Young
JY
Park
Se Jin
SJ
Jang
Jene
J
Choi
D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D000071636:Protein Phosphatase 2C; D020218:Response Elements / Q000235:genetics; D016160:Retinoblastoma Protein / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D047628:Estrogen Receptor alpha; D004967:Estrogens; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C