Sequential phosphorylation events drive G1 → S → G2 → M progression. Cyclin D + CDK4/6 phosphorylate Rb → releases E2F → S-phase entry. Cyclin E + CDK2 in late G1. Cyclin A + CDK2/1 in S/G2. Cyclin B + CDK1 in mitosis. p53 / p21 / p16 are major brakes. CDK4/6 INHIBITORS (palbociclib, ribociclib, abemaciclib) block G1 → S in HR+/HER2− metastatic breast cancer — synergistic with aromatase inhibitors or fulvestrant. AURORA + PLK1 kinases coordinate mitosis. Chemotherapy targets: taxanes stabilize microtubules (M); vinca alkaloids depolymerize (M); 5-FU / methotrexate hit S; etoposide blocks topo II in G2/M.
Organ Systems
immune-hematologic
reproductive
Pathway Steps
mitogen-signaling → cyclin-d-cdk4-6 — via growth factor → MAPK → cyclin D transcription. Mitogenic growth-factor signaling (via Ras-ERK and PI3K) induces D-type cyclins, which partner with CDK4/6 to form the first active kinase of the cycle. This makes cyclin D-CDK4/6 the node that links extracellular growth signals to the cell-cycle machinery — and the target of CDK4/6 inhibitors (palbociclib) in breast cancer.
cyclin-d-cdk4-6 → rb-phosphorylation — via CDK4/6 phosphorylates Rb — PALBOCICLIB TARGET. Cyclin D-CDK4/6 begins phosphorylating the retinoblastoma protein (Rb). Hypophosphorylated Rb is the brake on the cycle, so phosphorylating it starts to release that brake. Loss of Rb or its regulation is one of the most common lesions in cancer, removing this key restriction on proliferation.
rb-phosphorylation → e2f-release — via frees E2F → S-phase gene transcription. Once Rb is hyperphosphorylated (completed by cyclin E-CDK2), it releases the E2F transcription factors it had been sequestering. This is the molecular basis of the restriction point — after it the cell is committed to divide independent of mitogens, the cycle’s key irreversible decision.
e2f-release → s-phase-entry — via cyclin E + CDK2; DNA replication initiation. Freed E2F transcribes the genes needed for S phase — DNA-synthesis enzymes, replication factors, and cyclin E (positive feedback) — driving entry into DNA replication. This couples the Rb/E2F switch directly to genome duplication, the point of no return into the cycle.