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

Xiongbin Lu1, Thuy-Ai Nguyen, Sung-Hwan Moon

  • 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.

Cancer Metastasis Reviews
|February 13, 2008
PubMed

Insights

Wild-type p53-induced phosphatase 1 (Wip1) is a serine/threonine phosphatase with oncogenic activity. It suppresses tumor suppressors and regulates DNA damage response, contributing to human cancers when overexpressed.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Wild-type p53-induced phosphatase 1 (Wip1), a serine/threonine phosphatase, exhibits oncogenic activity.
  • Wip1 (PPM1D) is amplified and overexpressed in various human cancers, including breast and ovarian carcinomas.
  • Wip1 belongs to the type 2C phosphatases (PP2Cdelta) family.

Purpose of the Study:

  • To elucidate the oncogenic functions of Wip1 by identifying its target proteins.
  • To understand Wip1's role in regulating DNA damage response and tumor suppressor activity.
  • To investigate the mechanisms underlying Wip1's oncogenicity in human cancers.

Main Methods:

  • Identification of Wip1 target proteins.
  • Analysis of Wip1's dephosphorylation activity on key signaling molecules.
  • Evaluation of Wip1's impact on DNA damage response pathways (ATM/ATR).
  • Assessment of Wip1's effect on tumor suppressor proteins (p53, ATM, p16INK4a, ARF).

Main Results:

  • Wip1 dephosphorylates substrates of ATM and ATR kinases, regulating DNA damage response.
  • Wip1 suppresses the activity of critical tumor suppressors, including p53, ATM, p16INK4a, and ARF.
  • Wip1 cooperates with oncogenes in fibroblast transformation assays.
  • Suppression of p53, p38 MAP kinase, and ATM/ATR signaling pathways by Wip1 contributes to its oncogenicity.

Conclusions:

  • Wip1 is a key oncogenic phosphatase that promotes cancer development.
  • Wip1's ability to regulate DNA damage response and suppress tumor suppressors underlies its oncogenic potential.
  • Targeting Wip1 may offer a therapeutic strategy for cancers with Wip1 amplification and overexpression.

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