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The discovery of p21, the gene p53 switches on to halt cell division, which explained for the first time how the most commonly mutated cancer gene actually stops damaged cells from growing.
El-Deiry, Vogelstein and colleagues searched for genes activated by wild-type p53 and identified WAF1, now called CDKN1A or p21, whose expression was induced by wild-type but not mutant p53 in human cells. Introducing WAF1 into cancer cell lines suppressed their growth. Independently identified at the same time as an inhibitor of cyclin-dependent kinases, p21 turned out to be the link between p53 activation and arrest of the cell cycle at the G1 checkpoint.
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 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.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Tumour suppressor gene, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Tumour suppressor gene, The cell-cycle engine (cyclins & CDKs), CDK4/6, p53 / RB / cell-cycle checkpoint.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Tumour suppressor gene, Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Tumour suppressor gene, p53 / RB / cell-cycle checkpoint, TP53.
Shares p53 / RB / cell-cycle checkpoint, TP53.
Shares CDK4/6, p53 / RB / cell-cycle checkpoint.
Shares Bert Vogelstein, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
Shares CDK4/6, p53 / RB / cell-cycle checkpoint.