The type 2C phosphatase Wip1: An oncogenic regulator of tumor suppressor and DNA damage response pathways

• Published in: Cancer and metastasis reviews Vol. 27; no. 2; pp. 123 - 135
• Main Authors: Lu, Xiongbin, Nguyen, Thuy-Ai, Moon, Sung-Hwan, Darlington, Yolanda, Sommer, Matthias, Donehower, Lawrence A.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2008; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Transformation, Neoplastic; DNA Damage - physiology; Genes, Tumor Suppressor; Humans; Oncogene Proteins - physiology; Oncology; Phosphoprotein Phosphatases - physiology; Protein Phosphatase 2C; Signal Transduction - physiology; Wip1; ATM; PP2C; PPM1D; Serine/threonine phosphatase; p53
• ISSN: 0167-7659; 1573-7233
• DOI: 10.1007/s10555-008-9127-x

The W ild-type p53- i nduced p hosphatase 1, Wip1 (or PPM1D), is unusual in that it is a serine/threonine phosphatase with oncogenic activity. A member of the type 2C phosphatases (PP2Cδ), Wip1 has been shown to be amplified and overexpressed in multiple human cancer types, including breast and ovarian carcinomas. In rodent primary fibroblast transformation assays, Wip1 cooperates with known oncogenes to induce transformed foci. The recent identification of target proteins that are dephosphorylated by Wip1 has provided mechanistic insights into its oncogenic functions. Wip1 acts as a homeostatic regulator of the DNA damage response by dephosphorylating proteins that are substrates of both ATM and ATR, important DNA damage sensor kinases. Wip1 also suppresses the activity of multiple tumor suppressors, including p53, ATM, p16 INK4a and ARF. We present evidence that the suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 are important components of its oncogenicity when it is amplified and overexpressed in human cancers.