Trp53 regulates Notch 4 signaling through Mdm2

J Cell Sci. 2011 Apr 1;124(Pt 7):1067-76. doi: 10.1242/jcs.068965.

Abstract

Notch receptors and their ligands have crucial roles in development and tumorigenesis. We present evidence demonstrating the existence of an antagonistic relationship between Notch 4 and Trp53, which is controlled by the Mdm2-dependent ubiquitylation and degradation of the Notch receptor. We show that this signal-controlling mechanism is mediated by physical interactions between Mdm2 and Notch 4 and suggest the existence of a trimeric complex between Trp53, Notch 4 and Mdm2, which ultimately regulates Notch activity. Functional studies indicate that Trp53 can suppress NICD4-induced anchorage-independent growth in mammary epithelial cells and present evidence showing that Trp53 has a pivotal role in the suppression of Notch-associated tumorigenesis in the mammary gland.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Epithelial Cells / chemistry
  • Epithelial Cells / metabolism
  • Humans
  • Mice
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Receptor, Notch4
  • Receptors, Notch / chemistry
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Notch
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2