ClC-3 Chloride Channel Proteins Regulate the Cell Cycle by Up-regulating cyclin D1-CDK4/6 through Suppressing p21/p27 Expression in Nasopharyngeal Carcinoma Cells.

Dong Ye,Linyan Zhu,Hai Luo,Lixin Chen,Wencai Ye,Tim Jacob,Jianwen Mao,Lili Zou,Zhouyi Lai,Liwei Wang

doi:10.1038/srep30276

Dong Ye, Linyan Zhu + Show 8 more

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https://doi.org/10.1038/srep30276

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Abstract

It was shown in this study that knockdown of ClC-3 expression by ClC-3 siRNA prevented the activation of hypotonicity-induced chloride currents, and arrested cells at the G0/G1 phase in nasopharyngeal carcinoma CNE-2Z cells. Reconstitution of ClC-3 expression with ClC-3 expression plasmids could rescue the cells from the cell cycle arrest caused by ClC-3 siRNA treatments. Transfection of cells with ClC-3 siRNA decreased the expression of cyclin D1, cyclin dependent kinase 4 and 6, and increased the expression of cyclin dependent kinase inhibitors (CDKIs), p21 and p27. Pretreatments of cells with p21 and p27 siRNAs depleted the inhibitory effects of ClC-3 siRNA on the expression of CDK4 and CDK6, but not on that of cyclin D1, indicating the requirement of p21 and p27 for the inhibitory effects of ClC-3 siRNA on CDK4 and CDK6 expression. ClC-3 siRNA inhibited cells to progress from the G1 phase to the S phase, but pretreatments of cells with p21 and p27 siRNAs abolished the inhibitory effects of ClC-3 siRNA on the cell cycle progress. Our data suggest that ClC-3 may regulate cell cycle transition between G0/G1 and S phases by up-regulation of the expression of CDK4 and CDK6 through suppression of p21 and p27 expression.

Highlights

Cyclin D1–CDK4/CDK6 complex is required to promote the progress of cells from the G0/G1 phase to the S phase
Threshold kinase activity of Cyclin-dependent kinases (CDKs) is a crucial determinant of the cell cycle progression, and inhibition of CDK activity directly or indirectly by up-regulating cyclin-dependent kinase inhibitors (CDKIs) expression represents a rational approach to intervene with the uncontrolled proliferation of cancer cells[23]
It is well known that cyclins-CDKs-CDKIs play a central role in regulation of the cell cycle

Summary

Introduction

Cyclin D1–CDK4/CDK6 complex is required to promote the progress of cells from the G0/G1 phase to the S phase. Threshold kinase activity of CDKs is a crucial determinant of the cell cycle progression, and inhibition of CDK activity directly or indirectly by up-regulating CDKI expression represents a rational approach to intervene with the uncontrolled proliferation of cancer cells[23]. Interaction between ClC-3 and cyclin D1 exists, and cyclin D1 may regulate the functional activities and/or the expression of the ClC-3 chloride channel in the CNE-2Z cell (a poorly differentiated human nasopharyngeal carcinoma cell line)[24]. These data suggest that ClC-3 may regulate the cell cycle through modulation of the expression of the cyclin D1-CDKs (4, 6)-CDKIs signaling pathway. The requirement of p21 and p27 for the inhibitory action of ClC-3 siRNA on the cell cycle was investigated

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