title: Growth inhibition in G(1) and altered expression of cyclin D1 and p27(kip-1 )after forced connexin expression in lung and liver carcinoma cells.
abstract: Gap junctional intercellular communication (GJIC) and connexin expression are frequently decreased in neoplasia and may contribute to defective growth control and loss of differentiated functions. GJIC, in E9 mouse lung carcinoma cells and WB-aB1 neoplastic rat liver epithelial cells, was elevated by forced expression of the gap junction proteins, connexin43 (Cx43) and connexin32 (Cx32), respectively. Transfection of Cx43 into E9 cells increased fluorescent dye-coupling in the transfected clones, E9-2 and E9-3, to levels comparable to the nontransformed sibling cell line, E10, from which E9 cells originated. Transduction of Cx32 into WB-aB1 cells also increased dye-coupling in the clone, WB-a/32-10, to a level that was comparable to the nontransformed sibling cell line, WB-F344. The cell cycle distribution was also affected as a result of forced connexin expression. The percentage of cells in G(1)-phase increased and the percentage in S-phase decreased in E9-2 and WB-a/32-10 cells as compared to E9 and WB-aB1 cells. Concomitantly, these cells exhibited changes in G(1)-phase cell cycle regulators. E9-2 and WB-a/32-10 cells expressed significantly less cyclin D1 and more p27(kip-1) protein than E9 and WB-aB1 cells. Other growth-related properties (expression of platelet-derived growth factor receptor-beta, epidermal growth factor receptor, protein kinase C-alpha, protein kinase A regulatory subunit-Ialpha, and production of nitric oxide in response to a cocktail of pro-inflammatory cytokines) were minimally altered or unaffected. Thus, enhancement of connexin expression and GJIC in neoplastic mouse lung and rat liver epithelial cells restored G(1) growth control. This was associated with decreased expression of cyclin D1 and increased expression of p27(kip-1), but not with changes in other growth-related functions.
authors.affiliation: Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699, USA.
authors.forename: L
authors.initials: L
authors.lastname: Koffler
authors.forename: S
authors.initials: S
authors.lastname: Roshong
authors.forename: I
authors.initials: I
authors.lastname: Kyu Park
authors.forename: K
authors.initials: K
authors.lastname: Cesen-Cummings
authors.forename: D C
authors.initials: DC
authors.lastname: Thompson
authors.forename: L D
authors.initials: LD
authors.lastname: Dwyer-Nield
authors.forename: P
authors.initials: P
authors.lastname: Rice
authors.forename: C
authors.initials: C
authors.lastname: Mamay
authors.forename: A M
authors.initials: AM
authors.lastname: Malkinson
authors.forename: R J
authors.initials: RJ
authors.lastname: Ruch
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000473:pathology*; D002450:Cell Communication; D018797:Cell Cycle Proteins; D002455:Cell Division; D017630:Connexins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016207:Cytokines / Q000494:pharmacology; D004058:Diffusion; D005456:Fluorescent Dyes / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D000097002:Gap Junction beta-1 Protein
chemical_list: D018797:Cell Cycle Proteins; D017630:Connexins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016207:Cytokines; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D011494:Protein Kinases; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D000097002:Gap Junction beta-1 Protein; C493961:Cdkn1b protein, mouse; C493962:Cdkn1b protein, rat; C081624:connexin 42