Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis

Cell Death Differ. 2012 Nov;19(11):1761-8. doi: 10.1038/cdd.2012.57. Epub 2012 May 4.

Abstract

Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc(Min)-induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in Apc(Min) mice. Here we show that cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (Gadd45a) exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the proapoptotic functions of p53 that respond to activation of the β-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active β-catenin under conditions of an enhanced DNA damage response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Cell Cycle Proteins / metabolism*
  • Cell Transformation, Neoplastic
  • Checkpoint Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Repair
  • Genes, APC
  • Intestinal Polyposis / metabolism
  • Intestinal Polyposis / pathology
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Phosphoprotein Phosphatases / deficiency
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Phosphatase 2C
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Stem Cells / metabolism
  • Tumor Suppressor Protein p53 / metabolism
  • beta Catenin / metabolism

Substances

  • Cdkn2a protein, mouse
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • Gadd45a protein, mouse
  • Lgr5 protein, mouse
  • Nuclear Proteins
  • Receptors, G-Protein-Coupled
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Checkpoint Kinase 2
  • Chek2 protein, mouse
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Phosphoprotein Phosphatases
  • Ppm1d protein, mouse
  • Protein Phosphatase 2C