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Abstract
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.
Highlights
Been reported that Cx43 increases the expression level of p27, a member of the Cip/Kip family, and inhibits cell proliferation[13]
To elucidate this unexpected molecular relationship between Cx43 and p27, we examined whether reduced nuclear accumulation of p27 by overexpressed Cx43 is due to the prevention of the nuclear translocation of cyclin D1-CDK4-p27 complex by Cx43-Hsc[70] interaction, and whether G1/S transition is inhibited by Cx43
To study in more detail whether upregulation of Cx43 inhibits the cell proliferation of HuH-7 cells, which are derived from human hepatocellular carcinoma cells (HCCs) and express endogenous Cx43, HuH-7 cells were transfected with increased level of Cx43-expressing vector, Cx43-mRFP
Summary
Been reported that Cx43 increases the expression level of p27, a member of the Cip/Kip family, and inhibits cell proliferation[13]. Overexpression of Cx43 decreased the nuclear accumulation of both cyclin D1 and p2715 These findings led us to speculate that Cx43 would regulate the cyclin D1-CDK4-p27 complex via interaction with Hsc[70], and as a result, subcellular distribution of p27 would be regulated in Cx43-Hsc[70] interaction–mediated cell cycle suppression. To elucidate this unexpected molecular relationship between Cx43 and p27, we examined whether reduced nuclear accumulation of p27 by overexpressed Cx43 is due to the prevention of the nuclear translocation of cyclin D1-CDK4-p27 complex by Cx43-Hsc[70] interaction, and whether G1/S transition is inhibited by Cx43. Our findings suggest that Cx43-Hsc[70] interaction-mediated p27 subcellular distribution could be a novel mechanism in Cx43 regulating cell cycle progression
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