The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth

J Biol Chem. 2010 Mar 12;285(11):8472-80. doi: 10.1074/jbc.M109.069450. Epub 2010 Jan 11.

Abstract

The imprinted gene PEG3 confers parenting and sexual behaviors, alters growth and development, and regulates apoptosis. However, a molecular mechanism that can account for the diverse functions of Peg3/Pw1 is not known. To elucidate Peg3-regulated pathways, we performed a functional screen in zebrafish. Enforced overexpression of PEG3 mRNA during zebrafish embryogenesis decreased beta-catenin protein expression and inhibited Wnt-dependent tail development. Peg3/Pw1 also inhibited Wnt signaling in human cells by binding to beta-catenin and promoting its degradation via a p53/Siah1-dependent, GSK3beta-independent proteasomal pathway. The inhibition of the Wnt pathway by Peg3/Pw1 suggested a role in tumor suppression. Hypermethylation of the PEG3 promoter in primary human gliomas led to a loss of imprinting and decreased PEG3 mRNA expression that correlated with tumor grade. The decrease in Peg3/Pw1 protein expression increased beta-catenin, promoted proliferation, and inhibited p53-dependent apoptosis in human CD133(+) glioma stem cells. Thus, mammalian imprinting utilizes Peg3/Pw1 to co-opt the Wnt pathway, thereby regulating development and glioma growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Division / physiology
  • Cell Line, Tumor
  • DNA Methylation / physiology
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Genomic Imprinting / physiology*
  • Glioma / genetics
  • Glioma / metabolism
  • Glioma / pathology*
  • Humans
  • Kruppel-Like Transcription Factors / genetics*
  • Kruppel-Like Transcription Factors / metabolism*
  • Promoter Regions, Genetic / physiology
  • RNA, Messenger / metabolism
  • RNA, Messenger / pharmacology
  • Signal Transduction / physiology
  • Wnt Proteins / metabolism*
  • Zebrafish
  • beta Catenin / metabolism

Substances

  • CTNNB1 protein, human
  • Kruppel-Like Transcription Factors
  • PEG3 protein, human
  • RNA, Messenger
  • Wnt Proteins
  • beta Catenin