Contents

Search

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)

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: cytoplasm, nucleus 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]

Interactions

molecular events

Related

proliferating cell nuclear antigen (PCNA) WAF1 gene, PIC1, CIP1, SDI1

General

anti-oncoprotein (tumor suppressor protein) cyclin-dependent kinase inhibitor (CDKI, CDKN) nuclear protein phosphoprotein

Properties

COMPARTMENT: cytoplasm cell nucleus INHIBITS: protein kinase SIZE: entity length = 164 aa MW = 18 kD MOTIF: acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl Zn finger C4-type SITE: 13-41 EFFECTOR-BOUND: Zn+2 Ser phosphorylation site {S130} nuclear translocation signal {141-156} MOTIF: Thr phosphorylation site {T145} Ser phosphorylation site {S146} Ser phosphorylation site {S160}

References

  1. 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: 7973727
  2. Marx Science 266:1231 1994 [News & Views]
  3. 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: 8242751
  4. 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: 8242752
  5. Hunter T. Cooperation between oncogenes. Cell. 1991 Jan 25;64(2):249-70. Review. PMID: 1988147
  6. 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: 8125163
  7. Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: 7877684
  8. 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: 7665622
  9. 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: 7677168
  10. 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: 8657286
  11. 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: 12384701
  12. Entrez Gene :accession 1026
  13. UniProt :accession P38936
  14. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN1AID139.html
  15. NIEHS-SNPs http://egp.gs.washington.edu/data/cdkn1a/

Component-of

molecular complex

Databases & Figures

OMIM 116899 UniProt P38936 Pfam PF02234 Entrez Gene 1026 Kegg hsa:1026 Figures/diagrams/slides/tables related to cyclin-dependent kinase inhibitor 1