Interaction of Cx43 with Hsc70 regulates G1/S transition through CDK inhibitor p27.
Connexin 43 (Cx43) functions as a cell growth suppressor. We have demonstrated that Cx43 interacts with heat shock cognate protein 70 (Hsc70) for regulating cell proliferation. Hsc70 interacts with CDK inhibitor p27, which regulates the assembly and subcellular localization of cyclin D1-CDK4-p27 complex. However, the involvement of p27 with Cx43-mediated cell cycle suppression is still poorly understood. Here, we report that nuclear accumulation of p27 is reduced by overexpression of Cx43, and that this reduction is restored by co-overexpression with Hsc70. We found that Cx43 competes with p27 for binding to Hsc70, and as a result, decreases the level of Hsc70 in cyclin D1-CDK4-p27 complex, leading to prevention of the nuclear translocation of the complex and the G1/S transition. Collectively, our findings suggest that, in Cx43 up-regulation, which is most likely an emergency measure, Cx43-Hsc70 interaction regulates cell cycle G1/S progression through a novel mechanism by which Cx43-Hsc70 interaction prevents the nuclear accumulation of p27 through controlling the nuclear translocation of cyclin D1-CDK4-p27 complex.
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.|Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Hitoshi
H
Hino
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.|Department of Cellular Regenerative Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ping
P
Dai
Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tatsushi
T
Yoshida
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.|Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tomoya
T
Hatakeyama
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Yoshinori
Y
Harada
Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Eigo
E
Otsuji
Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tsukasa
T
Okuda
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tetsuro
T
Takamatsu
D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D018031:Connexin 43 / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D016193:G1 Phase; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D016196:S Phase; D015854:Up-Regulation
D018031:Connexin 43; D050883:HSC70 Heat-Shock Proteins; D046912:Multiprotein Complexes; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051358:Cyclin-Dependent Kinase 4