The STIM1-Orai1 pathway of store-operated Ca2+ entry controls the checkpoint in cell cycle G1/S transition.

Yun-Wen Chen,Wen-Tai Chiu,Yih-Fung Chen,Meng-Ru Shen,Ying-Ting Chen

doi:10.1038/srep22142

Abstract

Ca2+ signaling is important to trigger the cell cycle progression, while it remains elusive in the regulatory mechanisms. Here we show that store-operated Ca2+ entry (SOCE), mediated by the interaction between STIM1 (an endoplasmic reticulum Ca2+ sensor) and Orai1 (a cell membrane pore structure), controls the specific checkpoint of cell cycle. The fluctuating SOCE activity during cell cycle progression is universal in different cell types, in which SOCE is upregulated in G1/S transition and downregulated from S to G2/M transition. Pharmacological or siRNA inhibition of STIM1-Orai1 pathway of SOCE inhibits the phosphorylation of CDK2 and upregulates the expression of cyclin E, resulting in autophagy accompanied with cell cycle arrest in G1/S transition. The subsequently transient expression of STIM1 cDNA in STIM1−/− MEF rescues the phosphorylation and nuclear translocation of CDK2, suggesting that STIM1-mediated SOCE activation directly regulates CDK2 activity. Opposite to the important role of SOCE in controlling G1/S transition, the downregulated SOCE is a passive phenomenon from S to G2/M transition. This study uncovers SOCE-mediated Ca2+ microdomain that is the molecular basis for the Ca2+ sensitivity controlling G1/S transition.

Highlights

Regulation of the cell cycle involves the important processes for cell survival, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division
We reported that STIM- and Orai1-mediated Store-operated Ca2+ entry (SOCE) regulating G1/S transition seems to be ubiquitous in many different cell types
They reported that the kinase activity of cyclin E/CDK2 was responsive to functional changes in Ca2+ concentration

Summary

Introduction

Regulation of the cell cycle involves the important processes for cell survival, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The sequence of events that constitute the cell cycle is mainly regulated by extracellular signals and coordinated by internal checkpoints[1]. In response to various signals, cyclins and CDKs interact to form a complex that activates or inactivates target proteins to orchestrate coordinated entry into the phase of the cell cycle. STIM (stromal-interaction molecule) and Orai, are the molecular identities responsible for SOCE activation[7,8]. An essential pore-forming component of SOCE, translocates to the same STIM-containing structures during ER Ca2+ depletion and opens to mediate Ca2+ entry. Inactivation of SOCE by STIM1-silencing in smooth muscle cells, cervical and breast cancer cells significantly inhibited cell proliferation by slowing down the cell cycle progression[11,13]. We show that the activation of SOCE fluctuates during the cell cycle progression, in which the SOCE activity controls G1/S transition but is not necessary for S to G2/M transition

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Results

Conclusion