title: Unexpected role for the human Cx37 C1019T polymorphism in tumour cell proliferation.
abstract: Connexins are a large family of proteins that form gap junction channels allowing exchange of ions and small metabolites between neighboring cells. They have been implicated in pathological processes such as tumourigenesis in which they may act as tumour suppressors. A polymorphism in the human connexin37 (Cx37) gene (C1019T), resulting in a non-conservative amino acid change in the regulatory C-terminus (CT) of the Cx37 protein (P319S) has been suggested to be implicated in predisposition to angiosarcomas. In this study, we have used communication-deficient HeLa and SK-HEP-1 cells transfected with Cx37-319S, Cx37-319P or empty vector. We showed that the expression of Cx37-319P limited proliferation of HeLa and SK-HEP-1 cells, whereas Cx37-319S expression was without effect. Using an in vitro kinase assay, we demonstrated phosphorylation of Cx37 CT by glycogen synthase kinase-3 (GSK-3), a kinase known to be implicated in cell proliferation and cancer. GSK-3-induced phosphorylation was associated with reduced gap junctional intercellular communication (GJIC) as measured by microinjection of the tracer neurobiotin. Inhibition of GSK-3 by LiCl or SB415286 reduced phosphorylation of Cx37-319P and increased GJIC. This latter effect on GJIC involved the beta and not the alpha isoform of GSK-3. In contrast, GSK-3 inhibitors were without effect on HeLa cells expressing Cx37-319S. In conclusion, our data indicate functional effects of the Cx37 C1019T polymorphism on GJIC that might contribute to tumour cell growth.
authors: Department of Pathology and Immunology, University of Geneva, 64 avenue de la Roseraie, Geneva, Switzerland. sandrine.morel@unige.ch
authors: Sandrine
authors: S
authors: Morel
authors: Laurent
authors: L
authors: Burnier
authors: Angela
authors: A
authors: Roatti
authors: Alexandra
authors: A
authors: Chassot
authors: Isabelle
authors: I
authors: Roth
authors: Esther
authors: E
authors: Sutter
authors: Katia
authors: K
authors: Galan
authors: Anna
authors: A
authors: Pfenniger
authors: Marc
authors: M
authors: Chanson
authors: Brenda R
authors: BR
authors: Kwak
mesh_terms: D015153:Blotting, Western; D002450:Cell Communication; D002453:Cell Cycle; D049109:Cell Proliferation; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D010766:Phosphorylation; D011110:Polymorphism, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097006:Gap Junction alpha-4 Protein
chemical_list: D017630:Connexins; D038362:Glycogen Synthase Kinase 3; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000097006:Gap Junction alpha-4 Protein