El-Deiry 1993: WAF1, the gene through which p53 stops cell division
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.
Overview
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.
- WAF1 (p21, CDKN1A) was identified as a gene induced by wild-type p53 and not by tumour-derived mutant p53.
- Expression of WAF1 suppressed the growth of human tumour cell lines.
- p21 was shown by parallel work to inhibit cyclin-dependent kinases, providing the mechanism for p53-mediated cell cycle arrest.
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.
- Cell line study; the in vivo roles of p21 in tumour suppression proved more complex.
- p21 is also induced by p53-independent signals.
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.
Similar pages
not linked directly; found by shared links- Key paperVogelstein, Lane and Levine 2000: surfing the p53 network
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Bert Vogelstein, Tumour suppressor gene, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
- Key paperHollstein 1991: p53 mutations in human cancers
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Bert Vogelstein, Tumour suppressor gene, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center.
- TermHallmark: evading growth suppressors
Shares Tumour suppressor gene, The cell-cycle engine (cyclins & CDKs), CDK4/6, p53 / RB / cell-cycle checkpoint.
- TermApoptosis
Shares Levine 1997: p53, the cellular gatekeeper for growth and division, Tumour suppressor gene, p53 / RB / cell-cycle checkpoint, TP53.
- CompanyBulsara Bioworks
Shares p53 / RB / cell-cycle checkpoint, TP53.
- PersonPaul Nurse
Shares CDK4/6, p53 / RB / cell-cycle checkpoint.
- IdeaDegrade the damaged p53 protein rather than trying to repair it
Shares p53 / RB / cell-cycle checkpoint, TP53.
- IdeaExtend p53 reactivation beyond the Y220C mutation
Shares p53 / RB / cell-cycle checkpoint, TP53.