Aberrant Connexin 43 endocytosis by the carcinogen lindane involves activation of the ERK/mitogen-activated protein kinase pathway.
Although worldwide concerns have emerged about environmental factors that display carcinogenic and reprotoxic effects, little is known about the mechanism(s) by which these chemicals alter testicular function. Using the 42GPA9 Sertoli cell line, we recently reported that one widely used lipid-soluble pesticide, Lindane impairs gap junctional intercellular communication by promoting the intracellular localization of Connexin 43 (Cx43), a tumor suppressor. We showed here that this chemical triggered the accumulation of Cx43 within Rab5 positive endosomes. Interestingly, evidence is provided that Lindane-induced Cx43 endocytosis did not stem on alteration of Cx43 partition in lipid rafts. Lindane induced concomitantly Cx43 phosphorylation and activation of extracellular signal-regulated kinases (ERK) but not of JNK and p38 mitogen- activated protein kinases. Inhibition of ERK pathway by PD98059, a MEK1-specific inhibitor, prevented Lindane-induced Cx43 phosphorylation, restored Cx43 membranous localization and gap junction coupling. Altogether, these findings provide the first evidence that Lindane-altered Cx43 endocytosis requires ERK activation. Such inappropriate activation of the mitogenic MAPK pathway and inactivation of the tumor suppressor Cx43 by Lindane may participate in the promotion of neoplastic cell growth.
Mograbi
Baharia
B
INSERM EMI 00-09, IFR 50, Faculté de Médecine, Avenue de Valombrose, F-06107 Nice Cedex 02, France. mograbi@unice.fr
Corcelle
Elisabeth
E
Defamie
Norah
N
Samson
Michel
M
Nebout
Marielle
M
Segretain
Dominique
D
Fénichel
Patrick
P
Pointis
Georges
G
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D001556:Hexachlorocyclohexane / Q000633:toxicity*; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D018031:Connexin 43; D004791:Enzyme Inhibitors; D005419:Flavonoids; D001556:Hexachlorocyclohexane; D017346:Protein Serine-Threonine Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D020696:rab5 GTP-Binding Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one