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cyclin-dependent kinase

Biochemistry / Cell Biology (with Oncology and Pharmacology correlates)Hematologic/LymphaticBreastSkinCellular/Systemic (cell cycle regulation)

Summary

Cyclin-dependent kinases (CDKs) are serine/threonine kinases that drive the cell cycle and are active only when bound to their regulatory cyclin partner. Active cyclin-CDK complexes phosphorylate target proteins (e.g., Rb) to promote cell cycle progression. They are inhibited by CDK inhibitors (p21, p27, p16), and CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are used in HR+/HER2- breast cancer.

Detail

**Basics** - CDKs are serine/threonine protein kinases. Their levels stay relatively constant through the cell cycle. Their activity depends on binding a cyclin, whose levels rise and fall (cyclins are synthesized, then degraded by ubiquitin-proteasome). - Full activation also requires phosphorylation by CDK-activating kinase (CAK) and removal of inhibitory phosphates (by Cdc25 phosphatase).

**Cyclin-CDK pairs by phase** - G1: Cyclin D-CDK4/6 (growth-factor sensitive; the "start" of the cycle). - G1/S: Cyclin E-CDK2. - S: Cyclin A-CDK2. - G2/M: Cyclin B-CDK1 (also called MPF, M-phase promoting factor).

**Key mechanism: the Rb checkpoint (G1→S)** - Hypophosphorylated Rb binds E2F and holds it inactive. - Cyclin D-CDK4/6 and then cyclin E-CDK2 phosphorylate Rb. This releases E2F, which transcribes S-phase genes (cyclin E, cyclin A, DNA replication enzymes), and the cell passes the restriction point.

**Negative regulation (CDK inhibitors, CKIs)** - p21 (CIP/KIP family) is induced by p53 after DNA damage. It inhibits cyclin-CDK complexes and causes G1 arrest so DNA can be repaired. Loss of p53 allows damaged cells to enter S phase. - p27 (CIP/KIP family) also inhibits cyclin-CDK complexes. Low p27 is associated with a worse prognosis in some cancers. - p16/INK4a (INK4 family) specifically inhibits CDK4/6. It is frequently inactivated in melanoma (familial melanoma, CDKN2A), pancreatic cancer, and others.

**Clinical significance** - Cyclin D1 overexpression via t(11;14) is characteristic of mantle cell lymphoma (IgH-CCND1). Cyclin D1 is also amplified in some breast and esophageal cancers. - CDK4 amplification or mutation occurs in melanoma and some sarcomas/gliomas. - Loss of Rb (retinoblastoma, small cell lung cancer, osteosarcoma) or p53 (Li-Fraumeni) removes these checkpoints. - HPV E7 binds and inactivates Rb. E6 degrades p53. - Drugs: palbociclib, ribociclib, and abemaciclib are CDK4/6 inhibitors used with endocrine therapy for HR+/HER2- metastatic breast cancer. They cause G1 arrest and require functional Rb to work. Main adverse effects: neutropenia (palbociclib, ribociclib), QT prolongation (ribociclib), diarrhea (abemaciclib), and VTE (abemaciclib).

**High-yield pearls** - CDKs are constitutively present, and cyclins are the regulated component. - Checkpoints: G1/S (p53/p21/Rb), G2/M (DNA damage and unreplicated DNA), and the spindle assembly checkpoint (metaphase-anaphase). - Cyclin B-CDK1 drives mitotic entry (nuclear envelope breakdown, chromosome condensation). Cyclin B degradation by APC/C is required for mitotic exit.

Sources

  • First Aid for the USMLE Step 1 (Cell Cycle Phases and Regulation; Tumor suppressors; Breast cancer drugs)
  • Robbins & Cotran Pathologic Basis of Disease (Neoplasia: Cell cycle and cancer)
  • Lippincott Illustrated Reviews: Biochemistry
  • Alberts et al., Molecular Biology of the Cell (Cell Cycle chapter)
  • Pathoma (Fundamentals of Pathology), Neoplasia chapter
  • Sketchy Pharm/Pathology: CDK4/6 inhibitors

Reviewed by Medusa editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.