O-GlcNAc-glycosylation of beta-catenin regulates its nuclear localization and transcriptional activity.
Beta-catenin plays a role in intracellular adhesion and regulating gene expression. The latter role is associated with its oncogenic properties. Phosphorylation of beta-catenin controls its intracellular expression but mechanism/s that regulates the nuclear localization of beta-catenin is unknown. We demonstrate that O-GlcNAc glycosylation (O-GlcNAcylation) of beta-catenin negatively regulates its levels in the nucleus. We show that normal prostate cells (PNT1A) have significantly higher amounts of O-GlcNAcylated beta-catenin compared to prostate cancer (CaP) cells. The total nuclear levels of beta-catenin are higher in the CaP cells than PNT1A but only a minimal fraction of the nuclear beta-catenin in the CaP cells are O-GlcNAcylated. Increasing the levels of O-GlcNAcylated beta-catenin in the CaP cells with PUGNAc (O- (2-acetamido-2-deoxy-d-gluco-pyranosylidene) amino-N-phenylcarbamate) treatment is associated with a progressive decrease in the levels of beta-catenin in the nucleus. TOPFlash reporter assay and mRNA expressions of beta-catenin's target genes indicate that O-GlcNAcylation of beta-catenin results in a decrease in its transcriptional activity. We define a novel modification of beta-catenin that regulates its nuclear localization and transcriptional function.
Sayat
Ria
R
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Leber
Brian
B
Grubac
Vanja
V
Wiltshire
Lesley
L
Persad
Sujata
S
D000117:Acetylglucosamine / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D002277:Carcinoma / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006801:Humans; D008297:Male; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D051176:beta Catenin; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000117:Acetylglucosamine