The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.
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.
Jiang
Xiuli
X
Department of Neurosurgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Yu
Yi
Y
Yang
Hong Wei
HW
Agar
Nathalie Y R
NY
Frado
Laura
L
Johnson
Mark D
MD
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting / Q000502:physiology*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D051741:Kruppel-Like Transcription Factors; C490820:PEG3 protein, human; D012333:RNA, Messenger; D051153:Wnt Proteins; D051176:beta Catenin