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# 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

## Key points

- Cyclin D-CDK4/6 phosphorylates RB in G1; cyclin E-CDK2 completes the G1/S transition; cyclin B-CDK1 drives mitosis.
- CDK inhibitors: p16 (INK4 family) blocks CDK4/6; p21 and p27 (CIP/KIP family) block several CDKs.
- G1/S checkpoint: DNA damage activates p53, which induces p21 and arrests the cycle.
- G2/M checkpoint stops damaged cells before mitosis; the spindle checkpoint prevents unequal chromosome sorting.
- Cancer: cyclin D1 overexpression (mantle cell lymphoma, breast), CDK4 mutation or amplification, p16 loss (melanoma, pancreas), RB or TP53 loss.

## 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](https://durgical.com/en/conditions/non-hodgkin-lymphoma/) | Activates CDK4/6 in G1 | Overexpression, translocation t(11;14) | Mantle cell lymphoma, breast cancer |
| [CDK4](https://durgical.com/en/conditions/soft-tissue-sarcomas/) | Phosphorylates RB | Germline mutation or amplification | Familial melanoma (mutation); liposarcoma and glioblastoma (amplification) |
| [p16 (CDKN2A)](https://durgical.com/en/conditions/pancreatic-cancer/) | Inhibits CDK4/6 | Deletion or promoter methylation | Melanoma, pancreatic cancer |
| [RB](https://durgical.com/en/conditions/retinoblastoma/) | 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.

## Memory aid

D for Door: cyclin D opens the door of G1 by kicking RB aside; p16 and p53 are the bouncers that cancer fires.

## 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.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/general-pathology/the-cell-cycle-in-cancer-cyclins-cdks-and-checkpoints/)

## Related

- [Tumour suppressor genes: RB, TP53, APC, BRCA and the two-hit hypothesis](https://durgical.com/en/general-pathology/tumour-suppressor-genes-rb-tp53-apc-brca-and-the-two-hit-hypothesis/)
- [Oncogenes: RAS, MYC, HER2, BCR-ABL and the table to know](https://durgical.com/en/general-pathology/oncogenes-ras-myc-her2-bcr-abl-and-the-table-to-know/)
- [The hallmarks of cancer](https://durgical.com/en/general-pathology/the-hallmarks-of-cancer/)
- [Genomic instability: mismatch repair, BRCA and xeroderma pigmentosum](https://durgical.com/en/general-pathology/genomic-instability-mismatch-repair-brca-and-xeroderma-pigmentosum/)
- [Evading cell death and replicating without limit: BCL2 and telomerase](https://durgical.com/en/general-pathology/evading-cell-death-and-replicating-without-limit-bcl2-and-telomerase/)

## Related conditions

- [Breast cancer](https://durgical.com/en/conditions/breast-cancer/)
- [Melanoma](https://durgical.com/en/conditions/melanoma/)
- [Non-Hodgkin lymphoma](https://durgical.com/en/conditions/non-hodgkin-lymphoma/)
- [Retinoblastoma](https://durgical.com/en/conditions/retinoblastoma/)
- [Cervical cancer](https://durgical.com/en/conditions/cervical-cancer/)
- [Pancreatic cancer](https://durgical.com/en/conditions/pancreatic-cancer/)
- [Soft tissue sarcomas (liposarcoma, leiomyosarcoma, rhabdomyosarcoma)](https://durgical.com/en/conditions/soft-tissue-sarcomas/)

## Elsewhere in DurgiPedia

- [Cell cycle, mitosis and meiosis](https://durgical.com/en/histology/cell-cycle-mitosis-and-meiosis/)
- [DNA replication: the replication fork](https://durgical.com/en/biochemistry/topics/dna-replication-the-replication-fork/)
- [Oncogenes and tumour suppressor genes](https://durgical.com/en/biochemistry/topics/oncogenes-and-tumour-suppressor-genes/)

## Microorganisms

- [Human papillomavirus](https://durgical.com/en/microbiology/human-papillomavirus/)

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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](https://medlineplus.gov/genetics/gene/cdkn2a/) (MedlinePlus, US National Library of Medicine, 2026); [RB1 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/rb1/) (MedlinePlus, US National Library of Medicine, 2026); [TP53 gene: MedlinePlus Genetics](https://medlineplus.gov/genetics/gene/tp53/) (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/general-pathology/the-cell-cycle-in-cancer-cyclins-cdks-and-checkpoints/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/the-cell-cycle-in-cancer-cyclins-cdks-and-checkpoints/