The transition of cells into the S phase from the G0/G1 phase and into the M phase from the G2 phase are the 2 important rate-limiting phases, which are regulated by cyclin–cyclin-dependent protein kinase–cyclin kinase inhibitor pathways.[37] Studies on prostate cancer cells,[38] kidney cancer cells,[39] breast cancer cells,[40] and gastric cancer cells[41] have shown that metformin regulates the expression levels of G0/G1 regulatory proteins (e.g., cyclin D1, cyclin dependent kinase 4 (CDK4), and CDK6) in tumor cells, and causes G0/G1 phase cell cycle arrest. The gene discussed is CDK4; the disease is kidney cancer.