Wip1, an oncogene targeting tumor suppressors expressed in intestinal stem cells

Wip1 phosphatase (PPM1D) has oncogenic properties and is implicated in a variety of cancer types, including gastrointestinal. Like Mdm2, Wip1 normally functions to resolve stress responses, such as after DNA damage, and return the cell to its normal, unstressed state. It is expressed in somatic as well as stem cells, with relatively high expression in intestinal stem cells. Loss of normal APC function and other events early in the carcinogenic process trigger a stress-like state often referred to as oncogenic stress. Wip1 can dampen protective responses to such stress through dephosphorylation of key activating sites in important tumor suppressors, such as p53. Even normal levels of Wip1 affect tumor suppression, because Wip1-deficient mice are markedly tumor resistant in a variety of tumor-prone models, including APCmin. Unlike Mdm2-null mice, Wip1-null mice have a relatively mild phenotype, so development of Wip1 inhibitors may be well tolerated in vivo.