Figure 10

Expected accelerated cell growth mechanism of mutant human-derived CDK4, Cyclin D, and TERT over the multiple species. (A) Cell growth arrest under the cellular stress. The protein level of p16 increases under the senescence. The p16 protein will bind to the pocket of the CDK4, and negatively regulates the activity of CDK4-Cyclin D complex. The inactivated CDK4-Cyclin D complex cannot induce the phosphorylation of pRB and its inactivation. Under the intact condition of pRB, E2F is not released from the binding status, resulting in no transcription of the downstream and growth arrest of the cells. (B) Enhanced cellular proliferation with mutant CDK4, Cyclin D and TERT. Due to the R24C mutation of mutant human-derived CDK4, p16 protein cannot suppress the activity of protein complex of mutant CDK4 and human Cyclin D. The exogenously introduced human-derived CDK4-Cyclin D complex has high homology with the endogenous CDK4-Cyclin D, and can form the protein complex with endogenous pRB, and phosphorylation. Due to the phosphorylation and inactivation of pRB, the transcription factor, E2F, would be released from the complex and induce cell proliferation.