p21

CDKN1A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AXC, 2ZVV, 2ZVW, 4RJF, 5E0U
Identifiers
Aliases	CDKN1A, CAP20, CDKN1, CIP1, MDA-6, P21, SDI1, WAF1, p21CIP1, cyclin-dependent kinase inhibitor 1A, cyclin dependent kinase inhibitor 1A
External IDs	OMIM: 116899 MGI: 104556 HomoloGene: 333 GeneCards: CDKN1A
Gene ontology Molecular function • protein complex binding • protein kinase inhibitor activity • metal ion binding • protein binding • cyclin-dependent protein serine/threonine kinase inhibitor activity • ubiquitin protein ligase binding • cyclin binding • cyclin-dependent protein kinase activating kinase activity Cellular component • cytoplasm • cytosol • cyclin-dependent protein kinase holoenzyme complex • nucleoplasm • PCNA-p21 complex • perinuclear region of cytoplasm • nucleus Biological process • cellular response to extracellular stimulus • signal transduction by p53 class mediator • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • mitotic cell cycle arrest • cellular response to heat • regulation of cyclin-dependent protein serine/threonine kinase activity • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest • positive regulation of cell death • response to organic cyclic compound • negative regulation of cyclin-dependent protein serine/threonine kinase activity • stress-induced premature senescence • positive regulation of fibroblast proliferation • replicative senescence • response to hyperoxia • G1/S transition of mitotic cell cycle • response to corticosterone • cellular response to amino acid starvation • positive regulation of programmed cell death • negative regulation of apoptotic process • response to glucocorticoid • response to arsenic-containing substance • regulation of DNA biosynthetic process • regulation of protein import into nucleus, translocation • response to organic substance • negative regulation of gene expression • cellular response to DNA damage stimulus • negative regulation of G1/S transition of mitotic cell cycle • regulation of cell cycle • intrinsic apoptotic signaling pathway • cellular senescence • positive regulation of reactive oxygen species metabolic process • cellular response to UV-B • G2/M transition of mitotic cell cycle • positive regulation of B cell proliferation • negative regulation of cell growth • cell cycle arrest • response to organonitrogen compound • animal organ regeneration • regulation of mitotic cell cycle • intestinal epithelial cell maturation • cellular response to ionizing radiation • cell cycle • Ras protein signal transduction • negative regulation of phosphorylation • response to toxic substance • response to UV • response to X-ray • response to drug • negative regulation of cell proliferation • protein stabilization • positive regulation of cyclin-dependent protein kinase activity Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1026	12575
Ensembl	ENSG00000124762	ENSMUSG00000023067
UniProt	P38936	P39689
RefSeq (mRNA)	NM_078467 NM_000389 NM_001220777 NM_001220778 NM_001291549	NM_001111099 NM_007669
RefSeq (protein)	NP_000380.1 NP_001207706.1 NP_001207707.1 NP_001278478.1 NP_510867.1	NP_001104569.1 NP_031695.1
Location (UCSC)	Chr 6: 36.68 – 36.69 Mb	Chr 17: 29.09 – 29.1 Mb
PubMed search	[1]	[2]
Wikidata

View/Edit Human

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p21^Cip1 (alternatively p21^Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor that inhibits the complexes of CDK2 and CDK1. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.^[3][4][5][6]

Function

p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G₁ and S phase.^[7] In addition to growth arrest, p21 can mediate cellular senescence. One of the ways it was discovered was as a senescent cell-derived inhibitor. p21-activated kinases (PAKs) are also effectors for GTPases Cdc42 and Rac. These effectors are responsible for cell morphology, motility, survival, gene transcription, apoptosis, and hormone signaling along with other processes. PAK 1, a member of the PAK family, is known for its kinase activity and translocation into the nucleus, along with its association with chromatin. It can be concluded that PAK 1 is involved with gene transcription. PAK 1 is also known as a component of DNA damage response, which leads to cellular sensitivity to ionizing radiation.^[8]

The expression of this gene is tightly controlled by the tumor suppressor protein p53, through which this protein mediates the p53-dependent cell cycle G₁ phase arrest in response to a variety of stress stimuli.^[9] This was a major discovery in the early 1990s that revealed how cells stop dividing after being exposed to damaging agents such as radiation. p21, along with p27, is responsible for arrest cell cycle progression. The staining of these inhibitors has not commonly been looked at regardless of their affect on oncogenic functions within the cell.^[10]

Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced TNM stage (a classification of cancer staging that stands for: tumor size, describing nearby lymph nodes, and distant metastasis), depth of invasion and OS. A study on immunohistochemical markers in malignant thymic epithelial tumors shows that p21 expression has a negatively influenced survival and significantly correlated with WHO (World Health Organization) type B2/B3. When combined with low p27 and high p53, DFS (Disease-Free Survival) decreases.^[10]

Studies of human embryonic stem cells (hESCs) commonly report the nonfunctional p53-p21 axis of the G1/S checkpoint pathway, and its relevance for cell cycle regulation and the DNA damage response (DDR). p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.^[11]

p21 can also interact with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair.^[12] This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own.^[13] Two alternatively spliced variants, which encode an identical protein, have been reported.

Sometimes p21 is expressed without being induced by p53. This kind of induction plays a big role in p53 independent differentiation which is promoted by p21. Expression of p21 is mainly dependent on two factors 1) stimulus provided 2) type of the cell. Growth arrest by p21 can promote cellular differentiation. p21 therefore prevents cell proliferation.

Mice that lack the p21 gene gain the ability to regenerate lost appendages.^[14]

Clinical significance

p21 mediates the resistance of hematopoietic cells to an infection with HIV^[15] by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses.^[16]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.^[17][18]

Also, animals that were treated with PAK and PARP inhibiters did not show tumor growth.^[8]

Interactions

P21 has been shown to interact with:

• Nrf2^[19]
• BCCIP,^[20]
• CIZ1,^[21]
• CUL4A,^[22]
• CCNE1,^[23]
• CDK,^{[4][20][23][24][25]}
• DDB1,^[22]
• DTL,^[22]
• GADD45A,^[26][27]
• GADD45G,^[28][29]
• PCNA,^{[30][31][32][33][34][35][36][37]}
• PIM1,^[38]
• TK1,^[39] and
• TSG101.^[40]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. "Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1)".
4. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (November 1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases". Cell. 75 (4): 805–16. doi:10.1016/0092-8674(93)90499-G. PMID 8242751.
5. el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (November 1993). "WAF1, a potential mediator of p53 tumor suppression". Cell. 75 (4): 817–25. doi:10.1016/0092-8674(93)90500-P. PMID 8242752.
6. "p21 is a universal inhibitor of cyclin kinases.". Nature. 366: 701–4. Dec 1993. doi:10.1038/366701a0. PMID 8259214.
7. Gartel AL, Radhakrishnan SK (May 2005). "Lost in transcription: p21 repression, mechanisms, and consequences". Cancer Res. 65 (10): 3980–5. doi:10.1158/0008-5472.CAN-04-3995. PMID 15899785.
8. Villamar, Olga; Prudnikova, Tatiana Y.; Araiza-Olivera, Daniela; Perez-Plasencia, Carlos; Johnson, Neil; Bernhardy, Andrea J.; Slifker, Michael; Renner, Catherine; Chernoff, Jonathan (2016-10-12). "Reduced PAK1 activity sensitizes FA/BRCA-proficient breast cancer cells to PARP inhibition". Oncotarget. 7 (47). doi:10.18632/oncotarget.12576. ISSN 1949-2553.
9. Rodriguez R, Meuth M (January 2006). "Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress". Mol. Biol. Cell. 17 (1): 402–12. doi:10.1091/mbc.E05-07-0594. PMC 1345677. PMID 16280359.
10. Leisibach, Priska; Schneiter, Didier; Soltermann, Alex; Yamada, Yoshi; Weder, Walter; Jungraithmayr, Wolfgang (2016-02-09). "Prognostic value of immunohistochemical markers in malignant thymic epithelial tumors". Journal of Thoracic Disease. 8 (9): 2580–2591. doi:10.21037/jtd.2016.08.82. ISSN 2077-6624. PMC 5059354. PMID 27747012.
11. Dolezalova D, Mraz M, Barta T, Plevova K, Vinarsky V, Holubcova Z, Jaros J, Dvorak P, Pospisilova S, Hampl A (2012). "MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells". Stem Cells. 30 (7): 1362–72. doi:10.1002/stem.1108. PMID 22511267.
12. Xiong Y, Zhang H, Beach D (1992). "D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA". Cell. 71 (3): 505–14. doi:10.1016/0092-8674(92)90518-h. PMID 1358458.
13. Almond JB, Cohen GM (April 2002). "The proteasome: a novel target for cancer chemotherapy". Leukemia. 16 (4): 433–43. doi:10.1038/sj.leu.2402417. PMID 11960320.
14. Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E (March 2010). "Lack of p21 expression links cell cycle control and appendage regeneration in mice". Proc. Natl. Acad. Sci. U.S.A. 107 (13): 5845–50. doi:10.1073/pnas.1000830107. PMC 2851923. PMID 20231440. Lay summary – PhysOrg.com.
15. Zhang J, Scadden DT, Crumpacker CS (February 2007). "Primitive hematopoietic cells resist HIV-1 infection via p21". J. Clin. Invest. 117 (2): 473–81. doi:10.1172/JCI28971. PMC 1783820. PMID 17273559.
16. Chen H, Li C, Huang J, Cung T, Seiss K, Beamon J, Carrington MF, Porter LC, Burke PS, Yang Y, Ryan BJ, Liu R, Weiss RH, Pereyra F, Cress WD, Brass AL, Rosenberg ES, Walker BD, Yu XG, Lichterfeld M (April 2011). "CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21". J. Clin. Invest. 121 (4): 1549–60. doi:10.1172/JCI44539. PMID 21403397. Lay summary – Harvard Gazette.
17. Klopfleisch R, Gruber AD (August 2009). "Differential expression of cell cycle regulators p21, p27 and p53 in metastasizing canine mammary adenocarcinomas versus normal mammary glands". Res. Vet. Sci. 87 (1): 91–6. doi:10.1016/j.rvsc.2008.12.010. PMID 19185891.
18. Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD (2011). "Molecular carcinogenesis of canine mammary tumors: news from an old disease". Vet. Pathol. 48 (1): 98–116. doi:10.1177/0300985810390826. PMID 21149845.
19. Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD (June 2009). "Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response". Mol. Cell. 34 (6): 663–73. doi:10.1016/j.molcel.2009.04.029. PMC 2714804. PMID 19560419.
20. Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H (October 2000). "TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase". J. Biol. Chem. 275 (40): 31145–54. doi:10.1074/jbc.M003031200. PMID 10878006.
21. Mitsui K, Matsumoto A, Ohtsuka S, Ohtsubo M, Yoshimura A (October 1999). "Cloning and characterization of a novel p21(Cip1/Waf1)-interacting zinc finger protein, ciz1". Biochem. Biophys. Res. Commun. 264 (2): 457–64. doi:10.1006/bbrc.1999.1516. PMID 10529385.
22. Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (September 2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes Dev. 22 (18): 2496–506. doi:10.1101/gad.1676108. PMC 2546691. PMID 18794347.
23. McKenzie PP, Danks MK, Kriwacki RW, Harris LC (July 2003). "P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest". Cancer Res. 63 (13): 3840–4. PMID 12839982.
24. Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL (December 2002). "Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells". Mol. Cell. Biol. 22 (23): 8184–98. doi:10.1128/MCB.22.23.8184-8198.2002. PMC 134072. PMID 12417722.
25. Yam CH, Ng RW, Siu WY, Lau AW, Poon RY (January 1999). "Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2". Mol. Cell. Biol. 19 (1): 635–45. PMC 83921. PMID 9858587.
26. Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, Roller P, Fornace AJ, Zhan Q (July 2000). "The central region of Gadd45 is required for its interaction with p21/WAF1". Exp. Cell Res. 258 (1): 92–100. doi:10.1006/excr.2000.4906. PMID 10912791.
27. Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW (November 2000). "Identification of a functional domain in a GADD45-mediated G2/M checkpoint". J. Biol. Chem. 275 (47): 36892–8. doi:10.1074/jbc.M005319200. PMID 10973963.
28. Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA (January 2001). "Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control". J. Biol. Chem. 276 (4): 2766–74. doi:10.1074/jbc.M005626200. PMID 11022036.
29. Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A (August 1999). "A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth". J. Biol. Chem. 274 (35): 24766–72. doi:10.1074/jbc.274.35.24766. PMID 10455148.
30. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
31. Frouin I, Maga G, Denegri M, Riva F, Savio M, Spadari S, Prosperi E, Scovassi AI (October 2003). "Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners". J. Biol. Chem. 278 (41): 39265–8. doi:10.1074/jbc.C300098200. PMID 12930846.
32. Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y (February 1998). "Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen". Proc. Natl. Acad. Sci. U.S.A. 95 (4): 1392–7. doi:10.1073/pnas.95.4.1392. PMC 19016. PMID 9465025.
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34. Jónsson ZO, Hindges R, Hübscher U (April 1998). "Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen". EMBO J. 17 (8): 2412–25. doi:10.1093/emboj/17.8.2412. PMC 1170584. PMID 9545252.
35. Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J (October 1996). "Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA". Cell. 87 (2): 297–306. doi:10.1016/S0092-8674(00)81347-1. PMID 8861913.
36. Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ (May 2001). "A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome". EMBO J. 20 (10): 2367–75. doi:10.1093/emboj/20.10.2367. PMC 125454. PMID 11350925.
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Further reading

• Marone M, Bonanno G, Rutella S, Leone G, Scambia G, Pierelli L (2002). "Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21". Leuk. Lymphoma. 43 (1): 51–7. doi:10.1080/10428190210195. PMID 11908736.
• Fang JY, Lu YY (2002). "Effects of histone acetylation and DNA methylation on p21( WAF1) regulation". World J. Gastroenterol. 8 (3): 400–5. PMID 12046058.
• Tokumoto M, Tsuruya K, Fukuda K, Kanai H, Kuroki S, Hirakata H, Iida M (2003). "Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27". Nephrol. Dial. Transplant. 18 Suppl 3: iii9–12. doi:10.1093/ndt/gfg1003. PMID 12771291.
• Amini S, Khalili K, Sawaya BE (2004). "Effect of HIV-1 Vpr on cell cycle regulators". DNA Cell Biol. 23 (4): 249–60. doi:10.1089/104454904773819833. PMID 15142382.
• Zhang Z, Wang H, Li M, Rayburn E, Agrawal S, Zhang R (2005). "Novel MDM2 p53-independent functions identified through RNA silencing technologies". Ann. N. Y. Acad. Sci. 1058: 205–14. doi:10.1196/annals.1359.030. PMID 16394138.
• P. Sankaranarayanan, T. E. Schomay, K. A. Aiello and O. Alter (April 2015). "Tensor GSVD of Patient- and Platform-Matched Tumor and Normal DNA Copy-Number Profiles Uncovers Chromosome Arm-Wide Patterns of Tumor-Exclusive Platform-Consistent Alterations Encoding for Cell Transformation and Predicting Ovarian Cancer Survival". PLOS ONE. 10 (4): e0121396. doi:10.1371/journal.pone.0121396. PMC 4398562. PMID 25875127. AAAS EurekAlert! Press Release and NAE Podcast Feature.

External links

• Cyclin-Dependent Kinase Inhibitor p21 at the US National Library of Medicine Medical Subject Headings (MeSH)
• Drosophila dacapo - The Interactive Fly
• CDKN1A human gene location in the UCSC Genome Browser.
• CDKN1A human gene details in the UCSC Genome Browser.