p21

{{about|the p21^Cip1 protein|the p21/ras protein|Ras (protein)|other uses|}}

p21^Cip1 (alternatively p21^Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes,{{cite journal | vauthors = Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D | title = p21 is a universal inhibitor of cyclin kinases. | journal = Nature | volume = 366 | issue = 6456 | pages = 701–704 | date = Dec 1993 | pmid = 8259214 | doi = 10.1038/366701a0 | bibcode = 1993Natur.366..701X | s2cid = 4362507 }} though is primarily associated with inhibition of CDK2.{{cite journal | vauthors = Abbas T, Dutta A | title = p21 in cancer: intricate networks and multiple activities | journal = Nature Reviews. Cancer | volume = 9 | issue = 6 | pages = 400–414 | date = Jun 2009 | pmid = 19440234 | pmc = 2722839 | doi = 10.1038/nrc2657 }}{{cite journal | vauthors = Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ | title = The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases | journal = Cell | volume = 75 | issue = 4 | pages = 805–816 | date = November 1993 | pmid = 8242751 | doi = 10.1016/0092-8674(93)90499-G | doi-access = free }} p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest.{{cite journal | vauthors = el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B | title = WAF1, a potential mediator of p53 tumor suppression | journal = Cell | volume = 75 | issue = 4 | pages = 817–825 | date = November 1993 | pmid = 8242752 | doi = 10.1016/0092-8674(93)90500-P | doi-access = free }}{{cite journal | vauthors = Bunz F et al | title = Requirement for p53 and p21 to sustain G2 arrest after DNA damage | journal = Science | location = New York, N.Y. | volume = 282 | issue = 5393 | pages = 1497–1501 | date = Nov 1998 | pmid = 9822382 | doi = 10.1126/science.282.5393.1497 }}Waldman, Todd, Kenneth W. Kinzler, and Bert Vogelstein. "p21 is necessary for the p53-mediated G1 arrest in human cancer cells." Cancer research 55.22 (1995): 5187-5190. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.{{cite web | title = Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1) | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1026 }}

Function

= CDK inhibition =

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.{{cite journal | vauthors = Gartel AL, Radhakrishnan SK | title = Lost in transcription: p21 repression, mechanisms, and consequences | journal = Cancer Research | volume = 65 | issue = 10 | pages = 3980–3985 | date = May 2005 | pmid = 15899785 | doi = 10.1158/0008-5472.CAN-04-3995 | doi-access = free }}{{cite journal | vauthors = Deng C, Zhang P, Harper JW, Elledge SJ, Leder P | title = Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control | journal = Cell | volume = 82 | issue = 4 | pages = 675–684 | date = Aug 1995 | pmid = 7664346 | doi = 10.1016/0092-8674(95)90039-x | s2cid = 11927122 | doi-access = free }} The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57. Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in a region that blocks its ability to complex with cyclins and thus prevent CDK activation.{{cite journal | vauthors = Chen J et al | title = Cyclin-binding motifs are essential for the function of p21CIP1 | journal = Molecular and Cellular Biology | volume = 16 | issue = 9 | pages = 4673–4682 | date = Sep 1996 | pmid = 8756624 | pmc = 231467 | doi = 10.1128/mcb.16.9.4673 }}

Experiments looking at CDK2 activity within single cells have also shown p21 to be responsible for a bifurcation in CDK2 activity following mitosis, cells with high p21 enter a G₀/quiescent state, whilst those with low p21 continue to proliferate.{{cite journal | vauthors = Spencer S, Cappell S, Tsai FC, Overton K, Wang C, Meyer T | title = The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit | journal = Cell | volume = 155 | issue = 2 | pages = 369–383 | date = Oct 2013 | pmid = 24075009 | pmc = 4001917 | doi = 10.1016/j.cell.2013.08.062 }} Follow up work, found evidence that this bistability is underpinned by double negative feedback between p21 and CDK2, where CDK2 inhibits p21 activity via ubiquitin ligase activity.{{cite journal | vauthors = Overton KW, Spencer SL, Noderer WL, Meyer T, Wang CL | title = Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 41 | pages = E4386–E4393 | date = Oct 2014 | pmid = 25267623 | pmc = 4205626 | doi = 10.1073/pnas.1409797111 | bibcode = 2014PNAS..111E4386O | doi-access = free }}

= PCNA inhibition =

p21 interacts 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.{{cite journal | vauthors = Flores-Rozas H et al | title = Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 18 | pages = 8655–8659 | date = Aug 1994 | pmid = 7915843 | pmc = 44665 | doi = 10.1073/pnas.91.18.8655 | bibcode = 1994PNAS...91.8655F | doi-access = free }}{{cite journal | vauthors = Waga S et al | title = The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA | journal = Nature | volume = 369 | issue = 6481 | pages = 574–578 | date = Jun 1994 | pmid = 7911228 | doi = 10.1038/369574a0 | bibcode = 1994Natur.369..574W | s2cid = 4369548 }}{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | title = D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA | journal = Cell | volume = 71 | issue = 3 | pages = 505–514 | date = Oct 1992 | pmid = 1358458 | doi = 10.1016/0092-8674(92)90518-h | s2cid = 26475570 }} Specifically, p21 has a high affinity for the PIP-box binding region on PCNA,{{cite journal | vauthors = Warbrick E, Lane DP, Glover DM, Cox LS | title = Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair | journal = Oncogene | volume = 14 | issue = 19 | pages = 2313–2321 | date = May 1997 | pmid = 9178907 | doi = 10.1038/sj.onc.1201072 | doi-access = free }} binding of p21 to this region is proposed to block the binding of processivity factors necessary for PCNA dependent S-phase DNA synthesis, but not PCNA dependent nucleotide excision repair (NER).{{cite journal | vauthors = Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J | title = Structure of the C-Terminal Region of p21WAF1/CIP1 Complexed with Human PCNA | journal = Cell | volume = 87 | issue = 2 | pages = 297–306 | date = Oct 1996 | pmid = 8861913 | doi = 10.1016/s0092-8674(00)81347-1 | s2cid = 17461501 | doi-access = free }} As such, p21 acts as an effective inhibitor of S-phase DNA synthesis though permits NER, leading to the proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis.{{cite journal | vauthors = Podust VN, Podust LM, Goubin F, Ducommun B, Huebscher U | title = Mechanism of inhibition of proliferating cell nuclear antigen-dependent DNA synthesis by the cyclin-dependent kinase inhibitor p21 | journal = Biochemistry | volume = 34 | issue = 27 | pages = 8869–8875 | date = Jul 1995 | pmid = 7612628 | doi = 10.1021/bi00027a039 }}

= Apoptosis inhibition =

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.{{cite journal | vauthors = Almond JB, Cohen GM | title = The proteasome: a novel target for cancer chemotherapy | journal = Leukemia | volume = 16 | issue = 4 | pages = 433–443 | date = April 2002 | pmid = 11960320 | doi = 10.1038/sj.leu.2402417 | doi-access = free }} The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported.{{cite journal | vauthors = Rodriguez R, Meuth M | title = Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress | journal = Molecular Biology of the Cell | volume = 17 | issue = 1 | pages = 402–412 | date = January 2006 | pmid = 16280359 | pmc = 1345677 | doi = 10.1091/mbc.E05-07-0594 }}

Regulation

= p53 dependent response =

Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as the primary mediator of downstream cell cycle arrest. Notably, El-Deiry et al. identified a protein p21 (WAF1) which was present in cells expressing wild type p53 but not those with mutant p53, moreover constitutive expression of p21 led to cell cycle arrest in a number of cell types.{{cite journal | vauthors = El-Deiry W | title = WAF1, a potential mediator of p53 tumor suppression | journal = Cell | volume = 75 | issue = 4 | pages = 817–825 | date = Nov 1993 | pmid = 8242752 | doi = 10.1016/0092-8674(93)90500-p | doi-access = free }} Dulcic et al. also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21 was found bound to inactive cyclin E/CDK2 complexes.{{cite journal | vauthors = Dulić V et al | title = p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest | journal = Cell | volume = 76 | issue = 6 | pages = 1013–1023 | date = Mar 1994 | pmid = 8137420 | doi = 10.1016/0092-8674(94)90379-4 | s2cid = 34535969 }} Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice.{{cite journal | vauthors = Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ | title = Radiation-induced cell cycle arrest compromised by p21 deficiency | journal = Nature | volume = 377 | issue = 6549 | pages = 552–557 | date = Oct 1995 | pmid = 7566157 | doi = 10.1038/377552a0 | bibcode = 1995Natur.377..552B | s2cid = 4317521 }} Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage.

Recent work exploring p21 activation in response to DNA damage at a single-cell level have demonstrated that pulsatile p53 activity leads to subsequent pulses of p21, and that the strength of p21 activation is cell cycle phase dependent.{{cite journal | vauthors = Stewart-Ornstein J, Lahav G | title = Dynamics of CDKN1A in Single Cells Defined by an Endogenous Fluorescent Tagging Toolkit | journal = Cell Reports | volume = 14 | issue = 7 | pages = 1800–1811 | date = Feb 2016 | pmid = 26876176 | pmc = 5154611 | doi = 10.1016/j.celrep.2016.01.045 }} Moreover, studies of p21-levels in populations of cycling cells, not exposed to DNA damaging agents, have shown that DNA damage occurring in mother cell S-phase can induce p21 accumulation over both mother G2 and daughter G1 phases which subsequently induces cell cycle arrest;{{cite journal | vauthors = Barr AR, Cooper S, Heldt FS, Butera F, Stoy H, Mansfeld J, Novák B, Bakal C | title = DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression | journal = Nature Communications | volume = 8 | pages = 14728 | date = Mar 2017 | pmid = 28317845 | pmc = 5364389 | doi = 10.1038/ncomms14728 | bibcode = 2017NatCo...814728B }} this responsible for the bifurcation in CDK2 activity observed in Spencer et al..

= Degradation =

p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage. Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCF^Skp2 induces degradation of p21.{{cite journal | vauthors = Yu ZK, Gervais JL, Zhang H | title = Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21CIP1/WAF1 and cyclin D proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 19 | pages = 11324–11329 | date = Sep 1998 | pmid = 9736735 | pmc = 21641 | doi = 10.1073/pnas.95.19.11324 | bibcode = 1998PNAS...9511324Y | doi-access = free }}{{cite journal | vauthors = Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano M, Hershko A | title = Role of the SCFSkp2 Ubiquitin Ligase in the Degradation of p21Cip1 in S Phase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 25752–25757 | date = Jul 2003 | pmid = 12730199 | doi = 10.1074/jbc.m301774200 | doi-access = free }} Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4^Cdt2 degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication,{{cite journal | vauthors = Kim Y, Starostina NG, Kipreos ET | title = The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing | journal = Genes & Development | volume = 22 | issue = 18 | pages = 2507–2519 | date = Sep 2008 | pmid = 18794348 | pmc = 2546690 | doi = 10.1101/gad.1703708 }} as well as in response to UV irradiation.{{cite journal | vauthors = Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A | title = PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex | journal = Genes & Development | volume = 22 | issue = 18 | pages = 2496–2506 | date = Sep 2008 | pmid = 18794347 | pmc = 2546691 | doi = 10.1101/gad.1676108 }} Recent work has now found that in human cell lines SCF^Skp2 degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4^Cdt2 acts to degrade p21 at a much higher rate than SCF^Skp2 over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase.

Clinical significance

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 (overall survival rate). 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.{{cite journal | vauthors = Leisibach P, Schneiter D, Soltermann A, Yamada Y, Weder W, Jungraithmayr W | title = Prognostic value of immunohistochemical markers in malignant thymic epithelial tumors | journal = Journal of Thoracic Disease | volume = 8 | issue = 9 | pages = 2580–2591 | date = Sep 2016 | pmid = 27747012 | pmc = 5059354 | doi = 10.21037/jtd.2016.08.82 | doi-access = free }}

p21 mediates the resistance of hematopoietic cells to an infection with HIV{{cite journal | vauthors = Zhang J, Scadden DT, Crumpacker CS | title = Primitive hematopoietic cells resist HIV-1 infection via p21 | journal = The Journal of Clinical Investigation | volume = 117 | issue = 2 | pages = 473–481 | date = February 2007 | pmid = 17273559 | pmc = 1783820 | doi = 10.1172/JCI28971 }} 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.{{cite journal | vauthors = 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 | title = CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21 | journal = The Journal of Clinical Investigation | volume = 121 | issue = 4 | pages = 1549–1560 | date = April 2011 | pmid = 21403397 | pmc = 3069774 | doi = 10.1172/JCI44539 }}

{{cite news | vauthors = McGreevey S | title = Protein that helps battle HIV | date = March 14, 2011 | newspaper = Harvard Gazette | url = http://news.harvard.edu/gazette/story/2011/03/protein-that-helps-battle-hiv/ }}

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.{{cite journal | vauthors = Klopfleisch R, Gruber AD | title = Differential expression of cell cycle regulators p21, p27 and p53 in metastasizing canine mammary adenocarcinomas versus normal mammary glands | journal = Research in Veterinary Science | volume = 87 | issue = 1 | pages = 91–96 | date = August 2009 | pmid = 19185891 | doi = 10.1016/j.rvsc.2008.12.010 }}{{cite journal | vauthors = Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD | title = Molecular carcinogenesis of canine mammary tumors: news from an old disease | journal = Veterinary Pathology | volume = 48 | issue = 1 | pages = 98–116 | date = Jan 2011 | pmid = 21149845 | doi = 10.1177/0300985810390826 | s2cid = 206509356 }}

Mice that lack the p21 gene gain the ability to regenerate lost appendages.{{cite journal | vauthors = Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, Heber-Katz E | title = Lack of p21 expression links cell cycle control and appendage regeneration in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 13 | pages = 5845–5850 | date = March 2010 | pmid = 20231440 | pmc = 2851923 | doi = 10.1073/pnas.1000830107 | bibcode = 2010PNAS..107.5845B | doi-access = free }}

{{cite web | title = 1 gene lost = 1 limb regained? Scientists demonstrate mammalian regeneration through single gene deletion | date = March 15, 2010 | website = Medical Xpress | url = https://medicalxpress.com/news/2010-03-gene-lost-limb-regained-scientists.html }}

Interactions

P21 has been shown to interact with:

Nrf2{{cite journal | vauthors = Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD | title = Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response | journal = Molecular Cell | volume = 34 | issue = 6 | pages = 663–673 | date = June 2009 | pmid = 19560419 | pmc = 2714804 | doi = 10.1016/j.molcel.2009.04.029 }}
BCCIP,
CIZ1,{{cite journal | vauthors = Mitsui K, Matsumoto A, Ohtsuka S, Ohtsubo M, Yoshimura A | title = Cloning and characterization of a novel p21(Cip1/Waf1)-interacting zinc finger protein, ciz1 | journal = Biochemical and Biophysical Research Communications | volume = 264 | issue = 2 | pages = 457–464 | date = October 1999 | pmid = 10529385 | doi = 10.1006/bbrc.1999.1516 }}
CUL4A,{{cite journal | vauthors = Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A | title = PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex | journal = Genes & Development | volume = 22 | issue = 18 | pages = 2496–2506 | date = September 2008 | pmid = 18794347 | pmc = 2546691 | doi = 10.1101/gad.1676108 }}
CCNE1,
CDK,{{cite journal | vauthors = Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H | title = TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase | journal = Journal of Biological Chemistry | volume = 275 | issue = 40 | pages = 31145–31154 | date = October 2000 | pmid = 10878006 | doi = 10.1074/jbc.M003031200 | doi-access = free }}{{cite journal | vauthors = McKenzie PP, Danks MK, Kriwacki RW, Harris LC | title = P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest | journal = Cancer Research | volume = 63 | issue = 13 | pages = 3840–3844 | date = July 2003 | pmid = 12839982 }}{{cite journal | vauthors = Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL | title = Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells | journal = Molecular and Cellular Biology | volume = 22 | issue = 23 | pages = 8184–8198 | date = December 2002 | pmid = 12417722 | pmc = 134072 | doi = 10.1128/MCB.22.23.8184-8198.2002 }}{{cite journal | vauthors = Yam CH, Ng RW, Siu WY, Lau AW, Poon RY | title = Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2 | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 635–645 | date = January 1999 | pmid = 9858587 | pmc = 83921 | doi = 10.1128/mcb.19.1.635 }}
DDB1,
DTL,
GADD45A,{{cite journal | vauthors = Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, Roller P, Fornace AJ, Zhan Q | title = The central region of Gadd45 is required for its interaction with p21/WAF1 | journal = Experimental Cell Research | volume = 258 | issue = 1 | pages = 92–100 | date = July 2000 | pmid = 10912791 | doi = 10.1006/excr.2000.4906 }}{{cite journal | vauthors = Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, Wang XW | title = Identification of a functional domain in a GADD45-mediated G2/M checkpoint | journal = Journal of Biological Chemistry | volume = 275 | issue = 47 | pages = 36892–36898 | date = November 2000 | pmid = 10973963 | doi = 10.1074/jbc.M005319200 | doi-access = free }}
GADD45G,{{cite journal | vauthors = Azam N, Vairapandi M, Zhang W, Hoffman B, Liebermann DA | title = Interaction of CR6 (GADD45gamma ) with proliferating cell nuclear antigen impedes negative growth control | journal = Journal of Biological Chemistry | volume = 276 | issue = 4 | pages = 2766–2774 | date = January 2001 | pmid = 11022036 | doi = 10.1074/jbc.M005626200 | doi-access = free }}{{cite journal | vauthors = Nakayama K, Hara T, Hibi M, Hirano T, Miyajima A | title = A novel oncostatin M-inducible gene OIG37 forms a gene family with MyD118 and GADD45 and negatively regulates cell growth | journal = Journal of Biological Chemistry | volume = 274 | issue = 35 | pages = 24766–24772 | date = August 1999 | pmid = 10455148 | doi = 10.1074/jbc.274.35.24766 | doi-access = free }}
HDAC,{{cite journal | vauthors = Zupkovitz G, Lagger S, Martin D, Steiner M, Hagelkruys A, Seiser C, Schöfer C, Pusch O | title = Histone deacetylase 1 expression is inversely correlated with age in the short-lived fish Nothobranchius furzeri | journal = Histochemistry and Cell Biology | volume = 150 | issue = 3 | pages = 255–269 | date = 28 June 2018 | pmid = 29951776 | pmc = 6096771 | doi = 10.1007/s00418-018-1687-4 }}
PCNA,{{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–1178 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R | s2cid = 4427026 }}{{cite journal | vauthors = Frouin I, Maga G, Denegri M, Riva F, Savio M, Spadari S, Prosperi E, Scovassi AI | title = Human proliferating cell nuclear antigen, poly(ADP-ribose) polymerase-1, and p21waf1/cip1. A dynamic exchange of partners | journal = Journal of Biological Chemistry | volume = 278 | issue = 41 | pages = 39265–39268 | date = October 2003 | pmid = 12930846 | doi = 10.1074/jbc.C300098200 | doi-access = free }}{{cite journal | vauthors = Watanabe H, Pan ZQ, Schreiber-Agus N, DePinho RA, Hurwitz J, Xiong Y | title = Suppression of cell transformation by the cyclin-dependent kinase inhibitor p57KIP2 requires binding to proliferating cell nuclear antigen | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 4 | pages = 1392–1397 | date = February 1998 | pmid = 9465025 | pmc = 19016 | doi = 10.1073/pnas.95.4.1392 | bibcode = 1998PNAS...95.1392W | doi-access = free }}{{cite journal | vauthors = Fotedar R, Mossi R, Fitzgerald P, Rousselle T, Maga G, Brickner H, Messier H, Kasibhatla S, Hübscher U, Fotedar A | title = A conserved domain of the large subunit of replication factor C binds PCNA and acts like a dominant negative inhibitor of DNA replication in mammalian cells | journal = The EMBO Journal | volume = 15 | issue = 16 | pages = 4423–4433 | date = August 1996 | pmid = 8861969 | pmc = 452166 | doi = 10.1002/j.1460-2075.1996.tb00815.x }}{{cite journal | vauthors = Jónsson ZO, Hindges R, Hübscher U | title = Regulation of DNA replication and repair proteins through interaction with the front side of proliferating cell nuclear antigen | journal = The EMBO Journal | volume = 17 | issue = 8 | pages = 2412–2425 | date = April 1998 | pmid = 9545252 | pmc = 1170584 | doi = 10.1093/emboj/17.8.2412 }}{{cite journal | vauthors = Gulbis JM, Kelman Z, Hurwitz J, O'Donnell M, Kuriyan J | title = Structure of the C-terminal region of p21(WAF1/CIP1) complexed with human PCNA | journal = Cell | volume = 87 | issue = 2 | pages = 297–306 | date = October 1996 | pmid = 8861913 | doi = 10.1016/S0092-8674(00)81347-1 | s2cid = 17461501 | doi-access = free }}{{cite journal | vauthors = Touitou R, Richardson J, Bose S, Nakanishi M, Rivett J, Allday MJ | title = A degradation signal located in the C-terminus of p21WAF1/CIP1 is a binding site for the C8 alpha-subunit of the 20S proteasome | journal = The EMBO Journal | volume = 20 | issue = 10 | pages = 2367–2375 | date = May 2001 | pmid = 11350925 | pmc = 125454 | doi = 10.1093/emboj/20.10.2367 }}{{cite journal | vauthors = Yu P, Huang B, Shen M, Lau C, Chan E, Michel J, Xiong Y, Payan DG, Luo Y | title = p15(PAF), a novel PCNA associated factor with increased expression in tumor tissues | journal = Oncogene | volume = 20 | issue = 4 | pages = 484–489 | date = January 2001 | pmid = 11313979 | doi = 10.1038/sj.onc.1204113 | doi-access = free }}
PIM1,{{cite journal | vauthors = Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS | title = Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1593 | issue = 1 | pages = 45–55 | date = December 2002 | pmid = 12431783 | doi = 10.1016/S0167-4889(02)00347-6 | doi-access = free }}
TK1,{{cite journal | vauthors = Huang DY, Chang ZF | title = Interaction of human thymidine kinase 1 with p21(Waf1) | journal = The Biochemical Journal | volume = 356 | issue = Pt 3 | pages = 829–834 | date = June 2001 | pmid = 11389691 | pmc = 1221910 | doi = 10.1042/0264-6021:3560829 }} and
TSG101.{{cite journal | vauthors = Oh H, Mammucari C, Nenci A, Cabodi S, Cohen SN, Dotto GP | title = Negative regulation of cell growth and differentiation by TSG101 through association with p21(Cip1/WAF1) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 8 | pages = 5430–5435 | date = April 2002 | pmid = 11943869 | pmc = 122786 | doi = 10.1073/pnas.082123999 | bibcode = 2002PNAS...99.5430O | doi-access = free }}

References

External links

{{MeshName|Cyclin-Dependent+Kinase+Inhibitor+p21}}
[http://www.sdbonline.org/fly/newgene/dacapo1.htm Drosophila dacapo - The Interactive Fly]
{{UCSC genome browser|CDKN1A}}
{{UCSC gene details|CDKN1A}}
{{PDBe-KB2|P38936|Human Cyclin-dependent kinase inhibitor 1}}

Category:Cell cycle regulators

Category:Tumor suppressor genes

p21