Levine 1997: p53, the cellular gatekeeper for growth and division
The classic account of how the p53 protein senses DNA damage and other stress and then stops a cell dividing or makes it die, and why losing p53, as about half of cancers do, removes a central safeguard against cancer.
Overview
Levine's review described p53 as a transcription factor kept at low levels by MDM2 and stabilised by signals including DNA damage, hypoxia and oncogene activation. Activated p53 induces genes that arrest the cell cycle, chiefly p21, or trigger apoptosis, so that damaged cells are repaired or removed. The review explained how p53 mutation in roughly half of human cancers, inheritance of a mutant allele in Li-Fraumeni syndrome, and viral proteins that inactivate p53 all remove this checkpoint, and it set out the MDM2 feedback loop that later became a drug target.
- p53 is stabilised by DNA damage, hypoxia and oncogene activation and acts as a transcription factor.
- Its main outputs are cell cycle arrest through p21 and apoptosis, removing damaged cells.
- MDM2 binds and degrades p53 in a negative feedback loop; p53 is mutated in about half of human cancers and inherited mutation causes Li-Fraumeni syndrome.
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.
- Written before the discovery of many p53 targets and of gain-of-function effects of mutant p53.
- A review; specific mechanisms have been refined since.
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 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.
Similar pages
not linked directly; found by shared links- Key paperSherr and Roberts 1999: CDK inhibitors as regulators of the G1 phase
Shares El-Deiry 1993: WAF1, the gene through which p53 stops cell division, Cell cycle, Tumour suppressor gene, p53 / RB / cell-cycle checkpoint.
- PersonBert Vogelstein
Shares El-Deiry 1993: WAF1, the gene through which p53 stops cell division, Vogelstein, Lane and Levine 2000: surfing the p53 network, Hollstein 1991: p53 mutations in human cancers, TP53.
- TermHallmark: evading growth suppressors
Shares Tumour suppressor gene, The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53.
- TreatmentEprenetapopt
Shares The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53.
- CompanyBulsara Bioworks
Shares p53 / RB / cell-cycle checkpoint, TP53.
- TreatmentKRT-232
- TargetWEE1
Shares Cell cycle, The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint.
- IdeaDegrade the damaged p53 protein rather than trying to repair it
Shares p53 / RB / cell-cycle checkpoint, TP53.