Connexin43 reverses the phenotype of transformed cells and alters their expression of cyclin/cyclin-dependent kinases.
Communication between adjacent cells through gap junctions is believed to be involved in the regulation of cell proliferation. This stems in part from the observation that transfection and overexpression of connexin (cx) 32 or cx43 genes into neoplastic cells lead to normalization of growth and decrease their tumorigenicity. The molecular mechanism(s) responsible for this phenomenon has not been characterized. We transfected the rat cx43 gene into a phenotypically transformed dog kidney epithelial cell line, TRMP, and were successful in restoring gap junctional communication as measured by dye coupling. In addition, cx43-transfected clones reverted to a flat morphology and were sensitive to density-dependent inhibition of proliferation with their G1 and S phase duration almost doubled. These cx43-induced effects were coupled with a decreased expression of specific cell cycle regulatory genes critical to cell cycle progression in nonneoplastic cells including cyclin A, D1, D2, and the cyclin-dependent kinases (CDK) 5 and CDK6. The protein levels of cyclin E, CDK2, and CDK4 were not affected. These results suggest that overexpression of cx43 and the formation of gap junctions with the establishment of gap junctional communication can affect the phenotype of transformed cells and alter specific gene expressions involved in cell cycle regulation.
Chen
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SC
Cell and Molecular Biology Department, Pacific Northwest Research Foundation, Seattle, Washington 98122, USA.
Pelletier
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DB
Ao
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Boynton
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D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018031:Connexin 43 / Q000494:pharmacology*; D003260:Contact Inhibition / Q000187:drug effects; D006224:Cricetinae; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis* / Q000235:genetics; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D004285:Dogs; D004790:Enzyme Induction / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D017629:Gap Junctions / Q000187:drug effects* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007668:Kidney; D008099:Liver; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010641:Phenotype; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D014162:Transfection
D018031:Connexin 43; D016213:Cyclins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D018844:Cyclin-Dependent Kinases