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

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Calcium (Ca2+) signaling is vital for cell cycle progression.
• The precise regulatory mechanisms of Ca2+ in the cell cycle remain largely unknown.

Purpose of the Study:

• To investigate the role of store-operated calcium entry (SOCE) in cell cycle regulation.
• To elucidate the involvement of STIM1 and Orai1 in controlling cell cycle checkpoints.

Main Methods:

• Studied SOCE activity fluctuations across the cell cycle in various cell types.
• Utilized pharmacological and siRNA inhibition of the STIM1-Orai1 pathway.
• Assessed CDK2 phosphorylation and cyclin E expression.
• Performed transient STIM1 cDNA expression in STIM1(-/-) MEF cells.

Main Results:

• SOCE is upregulated during G1/S transition and downregulated from S to G2/M transition.
• Inhibition of SOCE leads to cell cycle arrest at G1/S by affecting CDK2 and cyclin E.
• STIM1-mediated SOCE activation directly regulates CDK2 activity and its nuclear translocation.
• Downregulation of SOCE from S to G2/M is a passive event.

Conclusions:

• SOCE, through the STIM1-Orai1 interaction, acts as a critical regulator of the G1/S cell cycle checkpoint.
• A STIM1-Orai1-mediated Ca2+ microdomain is the molecular basis for Ca2+ sensitivity controlling G1/S transition.
• Understanding SOCE's role provides insights into cell cycle control mechanisms.