Induction of breast cancer in wild type p53 cells by BRCA1-IRIS overexpression.
Cells ability to evade cell death and to proliferate post geno-/cell-toxic stresses, likely leads to formation of cancer. Activation of p38MAPK and p53 following these stresses help protect cells against cancer development by initiating apoptosis. The duration of p38MAPK and p53 activation is regulated by the WIP1 phosphatase. BRCA1-IRIS triggers WIP1 expression in p53-dependent and -independent manner. BRCA1-IRIS triggers the expression and cytoplasmic localization of the mRNA stabilization and translation inducer, HuR that binds p53 and PPM1D mRNA. Hence, BRCA1-IRIS overexpression inactivates p38MAPK and/or p53 by upregulating WIP1 expression. BRCA1-IRIS abrogation of the homeostatic balance maintained by p38MAPK-p53-WIP1 pathway suppressed cell death induced by a lethal dose of UVC, high dosages of etoposide or H2O2, and allowed cells to survive and proliferate post geno-/cell-toxic stresses. This mechanism represents a new link between geno-/cell-toxic stress and aggressive breast cancer formation in p53 wild-type cells.
Elshamy
Wael M
WM
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813, USA.
D019313:BRCA1 Protein / Q000378:metabolism*; D001943:Breast Neoplasms / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005609:Free Radicals / Q000009:adverse effects; D016158:Genes, p53; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D014466:Ultraviolet Rays / Q000009:adverse effects; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D005609:Free Radicals; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C