Separate domains of p21 involved in the inhibition of Cdk kinase and PCNA

• Published in: Nature (London) 1995-03, Vol.374 (6520), p.386-388
• Main Authors: Chen, Junjie, Jackson, Peter K., Kirschner, Marc W., Dutta, Anindya
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Biological and medical sciences; CDC2-CDC28 Kinases; Cell Division - drug effects; Cell Line, Transformed; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclins - pharmacology; Deoxyribonucleic acid; DNA; DNA Replication - drug effects; Escherichia coli; Fundamental and applied biological sciences. Psychology; Haplorhini; Humanities and Social Sciences; Humans; letter; Molecular and cellular biology; Molecular biology; multidisciplinary; Peptide Fragments - metabolism; Proliferating Cell Nuclear Antigen - drug effects; Proliferating Cell Nuclear Antigen - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proteins; Recombinant Fusion Proteins - metabolism; Science; Science (multidisciplinary); Simian virus 40 - genetics; Tumor Cells, Cultured; Xenopus; Xenopus Proteins
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/374386a0

THE protein p21 (WAF1, CIP1 or sdil), induced by the tumour-suppressor protein p53, interacts with and inhibits two different targets essential for cell-cycle progression 1–8 . One of these is the cyclin–Cdk family of kinases and the other is the essential DNA replication factor, proliferating-cell nuclear antigen (PCNA). We report here that separate domains of p21 are responsible for interacting with and inhibiting the two targets. An amino-terminal domain inhibits cyclin–Cdk kinases and a carboxyl-terminal domain inhibits PCNA. Using these separated domains, we have determined that p21 inhibits different biological systems through different targets. The PCNA-binding domain is sufficient for inhibition of DNA replication based on simian virus 40, whereas the Cdk2-binding domain is sufficient for inhibition of DNA replication based on Xenopus egg extract and for growth suppression in transformed human cells.