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

Sci Rep. 2016 Feb 26;6:22142. doi: 10.1038/srep22142.

Abstract

Ca(2+) signaling is important to trigger the cell cycle progression, while it remains elusive in the regulatory mechanisms. Here we show that store-operated Ca(2+) entry (SOCE), mediated by the interaction between STIM1 (an endoplasmic reticulum Ca(2+) 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 Ca(2+) microdomain that is the molecular basis for the Ca(2+) sensitivity controlling G1/S transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics*
  • Calcium / metabolism*
  • Calcium Channels / metabolism*
  • Calcium Signaling / physiology*
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cell Survival / genetics
  • Cyclin E / biosynthesis
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Endoplasmic Reticulum / metabolism
  • G1 Phase Cell Cycle Checkpoints / genetics
  • HeLa Cells
  • Humans
  • Mice
  • Mitosis / genetics*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • ORAI1 Protein / genetics
  • ORAI1 Protein / metabolism*
  • Phosphorylation / genetics
  • RNA Interference
  • RNA, Small Interfering / genetics
  • S Phase Cell Cycle Checkpoints / genetics
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*

Substances

  • Calcium Channels
  • Cyclin E
  • Neoplasm Proteins
  • ORAI1 Protein
  • ORAI1 protein, human
  • RNA, Small Interfering
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Calcium