PPM1D (Wip) is a serine/threonine phosphatase implicated in cell cycle control, spermatogenesis, and lymphoid cell function. The predicted 605-amino acid PPM1D protein contains 2 putative nuclear localization signals and 3 regions conserved in serine/threonine PP2C phosphatases, as well as characteristics of a type 2C phosphatase, including magnesium dependence and relative insensitivity to okadaic acid. PPM1D expression is induced in response to ionizing radiation in a p53-dependent manner. The accumulation of PPM1D mRNA following ionizing radiation is rapid and transient, and PPM1D protein is localized to the nucleus. PPM1D may contribute to growth inhibitory pathways activated in response to DNA damage in a p53-dependent manner. PPM1D inhibits phosphorylation of the p38 mitogen-activated (MAP)kinase protein. Through p38 MAPK, PPM1D modulates the CDKN2A tumor-suppressor locus. This gene is located in a chromosomal region known to be amplified in breast cancer, (located at 17q22-q23), is amplified in human breast tumor cell lines and in approximately 11% of primary breast tumors, and appears to lead to cell transformation by abrogating p53 tumor suppressor activity. Inactivation of the p38 MAPK through PPM1D overexpression resulting from PPM1D amplification may contributes to the development of human cancers by suppressing p53 activation. PPM1D null mice have increased susceptibility to pathogens and reduced male fertility and longevity.