Practice question

Orderly appearance and destruction of cyclins dictates CDK activation windows. Mitogenic stimulation through receptor tyrosine kinases activates Ras-MAPK cascade leading to transcription factor AP-1, Myc, and beta-catenin mediated induction of cyclin D1, D2, D3 genes. Cyclin D proteins accumulate throughout G1, assembling with CDK4 and CDK6 kinases whose activity requires mitogen-dependent stabilization and CAK phosphorylation. Cyclin D-CDK4/6 complexes phosphorylate retinoblastoma proteins at early sites, initiating limited E2F release and transcription of cyclin E. Cyclin E-CDK2 then completes hyperphosphorylation and drives origin licensing release. Although true S-phase DNA polymerase activation relies heavily on cyclin A-CDK2, cyclin D persistence into early S in presence of continuous growth factors sustains transcription of nucleotide synthesis enzymes, RFC, and histone genes needed for replication. Degradation of cyclin D later via SCF containing Fbxo4 and Fbxo31 ensures handoff to cyclin A-CDK2, prevents re-activation of G1 program during replication, and limits origin re-licensing, integrating extracellular signals with cell cycle commitment.