Negative regulation of p21 by beta-catenin/TCF signaling: a novel mechanism by which cell adhesion molecules regulate cell proliferation.
Cell proliferation is regulated in part by cell-cell interactions mediated by cadherin and connexin. Here we present evidence that these two molecules act synergistically to suppress HEK293 cell proliferation by prolonging the G2/M phase. This event was accompanied by expression of p21, a potent Cdc2 kinase inhibitor. Not surprisingly, there was a concomitant decline in Cdc2 kinase activity. beta-Catenin/TCF signaling, which was downregulated by overexpression of N-cadherin, was found to inhibit transactivation of p21 gene expression. The effect of N-cadherin on cell proliferation and p21 expression was augmented by co-expression of connexin-43. Moreover, the magnitude of the connexin's effect was dependent on its ability to mediate intercellular communication. We conclude, therefore, that two major components of cell-cell interaction synergistically regulate cell cycle progression in HEK293 cells by regulating p21 expression in a beta-catenin/TCF-dependent manner.
Kamei
Junko
J
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Toyofuku
Toshihiko
T
Hori
Masatsugu
M
D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology; D051176:beta Catenin
C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D018031:Connexin 43; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003598:Cytoskeletal Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin