cyclin-dependent kinase inhibitor 1; p21WAF1/CIP1; p21; CDK-interacting protein 1; melanoma differentiation-associated protein 6; MDA-6 (CDKN1A, CAP20, CDKN1, CIP1, MDA6, PIC1, SDI1, WAF1)
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Function
- role in p53 inhibition of cellular proliferation in response to DNA damage (putative)
- p21WAF1/CIP1 is a p53-induced gene product that blocks cell cycle progression in G1[8]
- p21WAF1/CIP1 inhibits kinase activity of multiple CDK complexes
- p21WAF1/CIP1 & related p27KIP1 inhibit preferentially CDK2 & CDK4-cyclin complexes[7]
- p21WAF1/CIP1 blocks DNA excision repair of UV- & alkylating agent-induced DNA damage through interaction with PCNA
- inhibition of DNA repair occurs through inhibition of DNA polymerase delta; inhibition is stoichiometric & overcome by excess PCNA
- thus p21WAF1/CIP1 inhibits function of PCNA in both DNA replication & nucleotide excision repair
- phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA
- p21WAF1/CIP1 can act as an inhibitor of stress activated protein kinases (c-Jun amino-terminal kinases)[10]
Structure
belongs to the CDI family
Compartment
Expression
- expressed in all adult human tissues, with 5-fold lower levels observed in the brain
- expression is induced by p53, mezerein (antileukemic compound) & interferon-beta
- expression of p21WAF1/CIP1 is largely under transcriptional control by p53, but may also be up-regulated by EGF & FGF[9]
- C-myc is recruited to the p21WAF1/Cip1 promoter by MIZ-1; this blocks p21WAF1/Cip1 induction by p53 & other activators.
- myc does not affect p53 binding but inhibits bound p53 from activating transcription[11]
More general terms
- phosphoprotein
- nuclear protein
- anti-oncoprotein (tumor suppressor protein)
- cyclin-dependent kinase inhibitor (CDKI, CDKN)
Additional terms
References
- ↑ Smith ML, Chen IT, Zhan Q, Bae I, Chen CY, Gilmer TM, Kastan MB, O'Connor PM, Fornace AJ Jr. Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science. 1994 Nov 25;266(5189):1376-80. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7973727
- ↑ Marx Science 266:1231 1994 [News & Views]
- ↑ Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993 Nov 19;75(4):805-16. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8242751
- ↑ el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993 Nov 19;75(4):817-25. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8242752
- ↑ Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1988147
- ↑ Noda A, Ning Y, Venable SF, Pereira-Smith OM, Smith JR. Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen. Exp Cell Res. 1994 Mar;211(1):90-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8125163
- ↑ 7.0 7.1 Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7877684
- ↑ 8.0 8.1 Pan ZQ, Reardon JT, Li L, Flores-Rozas H, Legerski R, Sancar A, Hurwitz J. Inhibition of nucleotide excision repair by the cyclin- dependent kinase inhibitor p21. J Biol Chem. 1995 Sep 15;270(37):22008-16. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7665622
- ↑ 9.0 9.1 Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7677168
- ↑ 10.0 10.1 Shim J, Lee H, Park J, Kim H, Choi EJ. A non-enzymatic p21 protein inhibitor of stress-activated protein kinases. Nature. 1996 Jun 27;381(6585):804-6. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8657286
- ↑ 11.0 11.1 Seoane J et al Myc suppression of the p21(Cip1) Cdk inhibitor influences the outcome of the p53 response to DNA damage. Nature. 2002 Oct 17;419(6908):729-34. Epub 2002 Oct 2. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12384701
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1026
- ↑ UniProt http://www.uniprot.org/uniprot/P38936.html
- ↑ Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN1AID139.html
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/cdkn1a/