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A gene whose normal job is to stop cells dividing or to make damaged cells die. Losing it removes a brake, so the cell can grow unchecked even without a stuck accelerator.
Because a cell has two copies of each gene, a tumour suppressor is usually only disabled when both copies are lost, by mutation, deletion, or silencing; people who inherit one faulty copy (BRCA1, TP53 in Li-Fraumeni, APC) are one step closer and develop cancer young. TP53, mutated in about half of all cancers, halts division and triggers apoptosis after DNA damage; RB1 gates the cell cycle; PTEN restrains the PI3K pathway. Lost genes cannot be directly targeted by a drug, so treatment exploits the consequences: PARP inhibitors kill BRCA-deficient cells, and MDM2 inhibitors reactivate p53 in tumours where it is present but suppressed.
In plain words · TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Showing the target this term concerns: TP53.
This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
This review is the textbook basis for the cyclin D-CDK4/6-RB axis that palbociclib, ribociclib and abemaciclib target in breast cancer, and for reading CDKN2A loss and cyclin D1 amplification in tumour genomes.
This review fixed the picture of p53 as the guardian of the genome that every textbook uses. It explains why TP53-mutant cancers are aggressive and hard to treat, why MDM2 inhibitors are being developed to reactivate wild-type p53, and why germline TP53 testing matters in families.
This paper closed the loop between DNA damage, p53 and the cell cycle machinery. p21 is now a standard marker of p53 activity, part of how chemotherapy and radiotherapy stop cells dividing, and a component of the senescence response that CDK4/6 inhibitors exploit.
This paper is why TP53 status is reported in almost every tumour genome and why mutational signatures can point to causes. Its idea that mutation patterns record exposures grew into the mutational signature field, and TP53 mutation remains a marker of shorter survival and a drug target still being pursued.
Shares Deletion, Gene, Somatic mutation theory of cancer, Driver mutation.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, Synthetic lethality, PARP, TP53.
Shares Proceedings of the National Academy of Sciences, Driver mutation, p53 / RB / cell-cycle checkpoint, TP53.
Shares Driver mutation, p53 / RB / cell-cycle checkpoint, PI3K / AKT / mTOR, BRCA1 / BRCA2 (HRD).
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, p53 / RB / cell-cycle checkpoint, TP53.
Shares Hallmark: evading growth suppressors, Levine 1997: p53, the cellular gatekeeper for growth and division, Vogelstein, Lane and Levine 2000: surfing the p53 network, p53 / RB / cell-cycle checkpoint.
Shares Sherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase, El-Deiry 1993: WAF1, the gene through which p53 stops cell division, Hallmark: evading growth suppressors, p53 / RB / cell-cycle checkpoint.