Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice

Mol Carcinog. 2006 Aug;45(8):594-604. doi: 10.1002/mc.20195.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics
  • Animals
  • Body Weight / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA Damage / genetics*
  • Insulin-Like Growth Factor I / analysis
  • Longevity / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phenotype
  • Phosphoprotein Phosphatases / genetics*
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Phosphatase 1
  • Protein Phosphatase 2C
  • Protein-Serine-Threonine Kinases / metabolism
  • Sex Factors
  • Tumor Suppressor Protein p53 / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Neoplasm Proteins
  • Tumor Suppressor Protein p53
  • Insulin-Like Growth Factor I
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Chek2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • PPM1D protein, human
  • Phosphoprotein Phosphatases
  • Ppm1d protein, mouse
  • Protein Phosphatase 1
  • Protein Phosphatase 2C