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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.
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.
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 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.
Shares El-Deiry 1993: WAF1, the gene through which p53 stops cell division, Cell cycle, Tumour suppressor gene, p53 / RB / cell-cycle checkpoint.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, p53 / RB / cell-cycle checkpoint, TP53.
Shares Tumour suppressor gene, The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53.
Shares The p53 network (guardian of the genome), p53 / RB / cell-cycle checkpoint, TP53.
Shares El-Deiry 1993: WAF1, the gene through which p53 stops cell division, Hollstein 1991: p53 mutations in human cancers, Vogelstein, Lane and Levine 2000: surfing the p53 network, Somatic mutation theory of cancer.
Shares p53 / RB / cell-cycle checkpoint, TP53.
Shares Li-Fraumeni syndrome (germline TP53), TP53-mutated (p53-abnormal), TP53.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, TP53.