Nannenga Bonnie, Lu Xiongbin, Dumble Melissa, Van Maanen Marc, Nguyen Thuy-Ai, Sutton Richard, Kumar T Rajendra, Donehower Lawrence A
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Mol Carcinog. 2006 Aug;45(8):594-604. doi: 10.1002/mc.20195.
The p53-induced serine/threonine phosphatase, protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D) (or wild-type p53-induced phosphatase 1 (Wip1)), exhibits oncogenic activity in vitro and in vivo. It behaves as an oncogene in rodent fibroblast transformation assays and is amplified and overexpressed in several human tumor types. It may contribute to oncogenesis through functional inactivation of p53. Here, we show that the oncogenic function of PPM1D is associated with its phosphatase activity. While overexpressed PPM1D may be oncogenic, PPM1D null mice are resistant to spontaneous tumors over their entire lifespan. This cancer resistance may be based in part on an augmented stress response following DNA damage. PPM1D null mice treated with ionizing radiation display increased p53 protein levels and increased phosphorylation of p38 MAP kinase, p53, checkpoint kinase 1 (Chk1), and checkpoint kinase 2 (Chk2) in their tissues compared to their wild-type (WT) counterparts. Male PPM1D null mice show a modest reduction in longevity, reduced serum insulin-like growth factor 1 (IGF-1) levels, and reduced body weight compared to WT mice. The PPM1D null mouse phenotypes indicate that PPM1D has a homeostatic role in abrogating the DNA damage response and may regulate aspects of male longevity.
p53诱导的丝氨酸/苏氨酸磷酸酶，即镁依赖性蛋白磷酸酶1Dδ亚型（PPM1D）（或野生型p53诱导的磷酸酶1（Wip1）），在体外和体内均表现出致癌活性。在啮齿动物成纤维细胞转化试验中，它表现为一种癌基因，并且在几种人类肿瘤类型中发生扩增和过表达。它可能通过p53的功能失活促进肿瘤发生。在此，我们表明PPM1D的致癌功能与其磷酸酶活性相关。虽然过表达的PPM1D可能具有致癌性，但PPM1D基因敲除小鼠在其整个寿命期内对自发性肿瘤具有抗性。这种抗癌能力可能部分基于DNA损伤后增强的应激反应。与野生型（WT）对照相比，经电离辐射处理的PPM1D基因敲除小鼠组织中的p53蛋白水平升高，p38丝裂原活化蛋白激酶、p53、检查点激酶1（Chk1）和检查点激酶2（Chk2）的磷酸化增加。与WT小鼠相比，雄性PPM1D基因敲除小鼠的寿命略有缩短，血清胰岛素样生长因子1（IGF-1）水平降低，体重减轻。PPM1D基因敲除小鼠的表型表明，PPM1D在消除DNA损伤反应中具有稳态作用，并且可能调节雄性寿命的某些方面。
