The cell cycle in cancer: cyclins, CDKs and checkpoints !
- Mechanism
Cells divide only when cyclin-CDK engines are switched on and checkpoints agree. Cancer jams the engines on and cuts the checkpoint wires.
Updated 2026-11-01
What it is
The cell cycle is driven by cyclins and their cyclin-dependent kinases (CDKs) and is restrained by CDK inhibitors and checkpoints that check the DNA before copying and before division. The G1/S transition, controlled by the cyclin D-CDK4/6-RB axis, is the step most often deregulated in cancer. Loss of checkpoints lets cells divide with damaged DNA, fuelling more mutations.
Step by step
- Growth factor signalling raises cyclin D levels in G1.
- Cyclin D-CDK4/6 phosphorylates RB, which releases E2F.
- E2F switches on genes for S phase, including cyclin E.
- Cyclin E-CDK2 further phosphorylates RB: the cell passes the restriction point and commits to copy its DNA.
- If DNA is damaged, ATM/ATR activate p53, which induces p21 and halts the cycle for repair or apoptosis.
- Cyclin B-CDK1 drives entry into mitosis once the G2/M checkpoint is satisfied.
- In cancer, any break in this chain (too much cyclin D, no p16, no RB, no p53) lets cells cycle without control.
Cell-cycle components altered in cancer
| Component | Normal role | Alteration in cancer | Example |
|---|---|---|---|
| Cyclin D1 | Activates CDK4/6 in G1 | Overexpression, translocation t(11;14) | Mantle cell lymphoma, breast cancer |
| CDK4 | Phosphorylates RB | Germline mutation or amplification | Familial melanoma (mutation); liposarcoma and glioblastoma (amplification) |
| p16 (CDKN2A) | Inhibits CDK4/6 | Deletion or promoter methylation | Melanoma, pancreatic cancer |
| RB | Holds E2F | Mutation, deletion, HPV E7 | Retinoblastoma, cervical cancer |
| p53 | Checkpoint arrest via p21 | Mutation, MDM2 amplification, HPV E6 | Most human cancers |
Clinical notes
- CDK4/6 inhibitors are used with hormonal therapy in hormone receptor-positive breast cancer.
- Many chemotherapy drugs act on specific cell-cycle phases, which explains damage to rapidly dividing normal tissues (marrow, mucosa, hair).
- p16 overexpression on immunohistochemistry is a surrogate for high-risk HPV in cervical and oropharyngeal lesions.
Test yourself
Think of the answer, then tap the question to see it.
Which cyclin-CDK complex first phosphorylates RB?
Cyclin D with CDK4 or CDK6, in G1.
How does p53 stop the cell cycle after DNA damage?
It induces transcription of p21, a CDK inhibitor that blocks the G1/S transition.
Why is p16 strongly expressed in HPV-related lesions?
HPV E7 inactivates RB; without RB feedback, the cell overproduces p16, which serves as a marker of transforming HPV infection.
What translocation overexpresses cyclin D1 and in which lymphoma?
t(11;14), placing CCND1 next to the immunoglobulin heavy chain gene, in mantle cell lymphoma.
Related
- Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis
- Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know
- The hallmarks of cancer
- Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum
- Evading cell death and replicating without limit: BCL2 and telomerase
Related conditions
- Breast cancer
- Melanoma
- Non-Hodgkin lymphoma
- Retinoblastoma
- Cervical cancer
- Pancreatic cancer
- Soft tissue sarcomas (liposarcoma, leiomyosarcoma, rhabdomyosarcoma)
Elsewhere in DurgiPedia
- Cell cycle, mitosis and meiosis
- DNA replication: the replication fork
- Oncogenes and tumour suppressor genes
Microorganisms
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: CDKN2A gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); RB1 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); TP53 gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.