The Imprinted Gene PEG3 Inhibits Wnt Signaling and Regulates Glioma Growth |
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Authors: | Xiuli Jiang Yi Yu Hong Wei Yang Nathalie Y. R. Agar Laura Frado Mark D. Johnson |
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Affiliation: | From the Department of Neurosurgery, Brigham and Women''s Hospital, and Harvard Medical School, Boston, Massachusetts 02115 |
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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 β-catenin protein expression and inhibited Wnt-dependent tail development. Peg3/Pw1 also inhibited Wnt signaling in human cells by binding to β-catenin and promoting its degradation via a p53/Siah1-dependent, GSK3β-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 β-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. |
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Keywords: | Apoptosis Cancer Neurobiology/Neuroscience Oncogene/β-Catenin Protein/Protein-Protein Interactions Tumor/Suppressor/p53 Tumor/Oncogene |
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