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

The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.

Author information

  • 1Department of Neurosurgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

PMID:
20064927
[PubMed - indexed for MEDLINE]
PMCID:
PMC2832996
Free PMC Article

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