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{{about|the p21<sup>Cip1</sup> protein|the p21/ras protein|Ras (protein)|other uses|}}
{{PBB_Controls
{{lowercase|title=p21}}
| update_page = yes
{{Infobox_gene}}
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'''p21<sup>Cip1</sup>''' (alternatively '''p21<sup>Waf1</sup>'''), 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,<ref name="pmid8259214">{{cite journal |vauthors=Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D | pmid = 8259214 | doi=10.1038/366701a0 | volume=366 | title=p21 is a universal inhibitor of cyclin kinases. | year = 1993 | journal=Nature | pages=701–4}}</ref> though is primarily associated with inhibition of [[CDK2]].<ref name="Abbas Dutta 2009 pp. 400–414">{{cite journal | last=Abbas | first=Tarek | last2=Dutta | first2=Anindya | title=p21 in cancer: intricate networks and multiple activities | journal=Nature Reviews Cancer | publisher=Springer Nature | volume=9 | issue=6 | year=2009 | pages=400–414 | url=https://doi.org/10.1038%2Fnrc2657 | doi=10.1038/nrc2657 | accessdate=2017-03-20| pmc=2722839 }}</ref><ref name="pmid8242751">{{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 = 805–16 | date = November 1993 | pmid = 8242751 | doi = 10.1016/0092-8674(93)90499-G }}</ref> p21 represents a major target of [[TP53|p53]] activity and thus is associated with linking DNA damage to cell cycle arrest.<ref name="pmid8242752">{{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 = 817–25  | date = November 1993 | pmid = 8242752 | doi = 10.1016/0092-8674(93)90500-P }}</ref><ref name="Bunz">{{cite journal | vauthors = Bunz F ''et al'' | year = 1998 | title = Requirement for p53 and p21 to sustain G2 arrest after DNA damage | url = | journal = Science | volume = 282 | issue = 5393| pages = 1497–1501 | doi=10.1126/science.282.5393.1497}}</ref><ref name="Waldman">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.</ref> This protein is encoded by the ''CDKN1A'' [[gene]] located on [[chromosome 6]] (6p21.2) in humans.<ref name = "entrez">{{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| accessdate = }}</ref>
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== Function ==
}}
 
'''Cyclin-dependent kinase inhibitor 1A (p21, Cip1)''', also known as '''CDKN1A''', is a human [[gene]].
=== CDK inhibition ===
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{{GNF_Protein_box
p21 is a potent [[cyclin-dependent kinase inhibitor]] (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of [[cyclin]]-[[Cyclin-dependent kinase 2|CDK2]], -[[Cyclin-dependent kinase 1|CDK1]], and -[[cyclin-dependent kinase 4|CDK4]][[cyclin-dependent kinase 6|/6]] complexes, and thus functions as a regulator of [[cell cycle]] progression at [[Cell cycle checkpoint#G1 .28Restriction.29 Checkpoint|G<sub>1</sub>]] and [[S phase]].<ref name="pmid15899785">{{cite journal | vauthors = Gartel AL, Radhakrishnan SK | title = Lost in transcription: p21 repression, mechanisms, and consequences | journal = Cancer Res. | volume = 65 | issue = 10 | pages = 3980–5  | date = May 2005 | pmid = 15899785 | doi = 10.1158/0008-5472.CAN-04-3995 }}</ref><ref name="Deng Zhang Harper Elledge 1995 pp. 675–684">{{cite journal | last=Deng | first=Chuxia | last2=Zhang | first2=Pumin | last3=Harper | first3=J. Wade | last4=Elledge | first4=Stephen J. | last5=Leder | first5=Philip | title=Mice Lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control | journal=Cell | publisher=Elsevier BV | volume=82 | issue=4 | year=1995 | pages=675–684 | url=https://doi.org/10.1016%2F0092-8674%2895%2990039-x | doi=10.1016/0092-8674(95)90039-x | accessdate=2017-03-20}}</ref> 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 (gene)|p27]] and [[p57 (gene)|p57]].<ref name="Abbas Dutta 2009 pp. 400–414"/> 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.<ref>{{cite journal | vauthors = Chen J ''et al'' | year = 1996 | title = Cyclin-binding motifs are essential for the function of p21CIP1 | url = | journal = Molecular and Cellular Biology | volume = 16 | issue = 9| pages = 4673–4682 | doi=10.1128/mcb.16.9.4673| pmc = 231467}}</ref>
| image =
 
| image_source =
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 phase|G<sub>0</sub>/quiescent]] state, whilst those with low p21 continue to proliferate.<ref name="Spencer Cappell Tsai Overton 2013 pp. 369–383">{{cite journal | last=Spencer | first=Sabrina~L. | last2=Cappell | first2=Steven~D. | last3=Tsai | first3=Feng-Chiao | last4=Overton | first4=K.~Wesley | last5=Wang | first5=Clifford~L. | last6=Meyer | first6=Tobias | title=The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit | journal=Cell | publisher=Elsevier BV | volume=155 | issue=2 | year=2013 | pages=369–383 | url=https://doi.org/10.1016%2Fj.cell.2013.08.062 | doi=10.1016/j.cell.2013.08.062 | accessdate=2017-03-20}}</ref> 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.<ref name="Overton Spencer Noderer Meyer 2014 pp. E4386–E4393">{{cite journal | last=Overton | first=K. W. | last2=Spencer | first2=S. L. | last3=Noderer | first3=W. L. | last4=Meyer | first4=T. | last5=Wang | first5=C. L. | title=Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states | journal=Proceedings of the National Academy of Sciences | publisher=Proceedings of the National Academy of Sciences | volume=111 | issue=41 | year=2014 | pages=E4386–E4393 | url=https://doi.org/10.1073%2Fpnas.1409797111 | doi=10.1073/pnas.1409797111 | accessdate=2017-03-20| pmc=4205626 }}</ref>
| PDB =  
 
| Name = Cyclin-dependent kinase inhibitor 1A (p21, Cip1)
=== PCNA inhibition ===
| HGNCid = 1784
 
| Symbol = CDKN1A
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.<ref>{{cite journal | vauthors = Flores-Rozas H ''et al'' | year = 1994 | title = Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme | url = | journal = Proceedings of the National Academy of Sciences | volume = 91 | issue = 18| pages = 8655–8659 | doi=10.1073/pnas.91.18.8655| pmc = 44665}}</ref><ref>{{cite journal | vauthors = Waga S ''et al'' | year = 1994 | title = The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA | url = | journal = Nature | volume = 369 | issue = 6481| page = 574 | doi=10.1038/369574a0}}</ref><ref name="pmid1358458">{{cite journal | vauthors = Xiong Y, Zhang H, Beach D | year = 1992 | title = D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA | url = | journal = Cell | volume = 71 | issue = 3| pages = 505–14 | pmid = 1358458 | doi=10.1016/0092-8674(92)90518-h}}</ref> Specifically, p21 has a high affinity for the PIP-box binding region on PCNA,<ref>{{cite journal | vauthors = Warbrick E, Lane DP, Glover DM, Cox LS | year = 1997 | 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 | url = | journal = Oncogene | volume = 14 | issue = 19| pages = 2313–2321 | doi=10.1038/sj.onc.1201072 | pmid=9178907}}</ref> 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).<ref name="Gulbis Kelman Hurwitz ODonnell 1996 pp. 297–306">{{cite journal | last=Gulbis | first=Jacqueline M | last2=Kelman | first2=Zvi | last3=Hurwitz | first3=Jerard | last4=O'Donnell | first4=Mike | last5=Kuriyan | first5=John | title=Structure of the C-Terminal Region of p21WAF1/CIP1 Complexed with Human PCNA | journal=Cell | publisher=Elsevier BV | volume=87 | issue=2 | year=1996 | pages=297–306 | url=https://doi.org/10.1016%2Fs0092-8674%2800%2981347-1 | doi=10.1016/s0092-8674(00)81347-1 | accessdate=2017-03-20 | pmid=8861913}}</ref> As such, p21 acts as an effective inhibitor of DNA 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.<ref>{{cite journal | vauthors = Podust VN, Podust LM, Goubin F, Ducommun B, Huebscher U | year = 1995 | title = Mechanism of inhibition of proliferating cell nuclear antigen-dependent DNA synthesis by the cyclin-dependent kinase inhibitor p21 | url = | journal = Biochemistry | volume = 34 | issue = 27| pages = 8869–8875 | doi=10.1021/bi00027a039}}</ref>
| AltSymbols =; CAP20; CDKN1; CIP1; MDA-6; P21; SDI1; WAF1; p21CIP1
 
| OMIM = 116899
=== Apoptosis inhibition ===
| ECnumber =
 
| Homologene = 333
This protein was reported to be specifically cleaved by [[CASP3]]-like [[caspase]]s, 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.<ref name="pmid11960320">{{cite journal | vauthors = Almond JB, Cohen GM | title = The proteasome: a novel target for cancer chemotherapy | journal = Leukemia | volume = 16 | issue = 4 | pages = 433–43  | date = April 2002 | pmid = 11960320 | doi = 10.1038/sj.leu.2402417 }}</ref> The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported.<ref name="pmid16280359">{{cite journal | vauthors = Rodriguez R, Meuth M | title = Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress | journal = Mol. Biol. Cell | volume = 17 | issue = 1 | pages = 402–12  | date = January 2006 | pmid = 16280359 | pmc = 1345677 | doi = 10.1091/mbc.E05-07-0594 }}</ref>
| MGIid = 104556
 
| GeneAtlas_image1 = PBB_GE_CDKN1A_202284_s_at.png
== Regulation ==
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| DateOfBotUpdate = 23:01, 14 September 2007 (UTC)
=== p53 dependent response ===
| Function = {{GNF_GO|id=GO:0004672 |text = protein kinase activity}} {{GNF_GO|id=GO:0004861 |text = cyclin-dependent protein kinase inhibitor activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016301 |text = kinase activity}} {{GNF_GO|id=GO:0030332 |text = cyclin binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
 
  | Component = {{GNF_GO|id=GO:0000307 |text = cyclin-dependent protein kinase holoenzyme complex}} {{GNF_GO|id=GO:0005634 |text = nucleus}}
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.<ref name="El-Deiry 1993 pp. 817–825">{{cite journal | last=El-Deiry | first=W | title=WAF1, a potential mediator of p53 tumor suppression | journal=Cell | publisher=Elsevier BV | volume=75 | issue=4 | year=1993 | pages=817–825 | url=https://doi.org/10.1016%2F0092-8674%2893%2990500-p | doi=10.1016/0092-8674(93)90500-p | accessdate=2017-03-20 | pmid=8242752}}</ref> 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.<ref>{{cite journal | vauthors = Dulić V ''et al'' | year = 1994 | title = p53-dependent inhibition of cyclin-dependent kinase activities in human fibroblasts during radiation-induced G1 arrest | url = | journal = Cell | volume = 76 | issue = 6| pages = 1013–1023 | doi=10.1016/0092-8674(94)90379-4}}</ref> 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.<ref name="Brugarolas Chandrasekaran Gordon Beach 1995 pp. 552–557">{{cite journal | last=Brugarolas | first=James | last2=Chandrasekaran | first2=Chitra | last3=Gordon | first3=Jeffrey I. | last4=Beach | first4=David | last5=Jacks | first5=Tyler | last6=Hannon | first6=Gregory J. | title=Radiation-induced cell cycle arrest compromised by p21 deficiency | journal=Nature | publisher=Springer Nature | volume=377 | issue=6549 | year=1995 | pages=552–557 | url=https://doi.org/10.1038%2F377552a0 | doi=10.1038/377552a0 | accessdate=2017-03-20}}</ref><ref name="Deng Zhang Harper Elledge 1995 pp. 675–684" /> Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage.
| Process = {{GNF_GO|id=GO:0006974 |text = response to DNA damage stimulus}} {{GNF_GO|id=GO:0007049 |text = cell cycle}} {{GNF_GO|id=GO:0007050 |text = cell cycle arrest}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0008629 |text = induction of apoptosis by intracellular signals}} {{GNF_GO|id=GO:0009411 |text = response to UV}} {{GNF_GO|id=GO:0030890 |text = positive regulation of B cell proliferation}} {{GNF_GO|id=GO:0043066 |text = negative regulation of apoptosis}} {{GNF_GO|id=GO:0043071 |text = positive regulation of non-apoptotic programmed cell death}} {{GNF_GO|id=GO:0045736 |text = negative regulation of cyclin-dependent protein kinase activity}}
 
| Orthologs = {{GNF_Ortholog_box
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.<ref name="Stewart-Ornstein Lahav 2016 pp. 1800–1811">{{cite journal | last=Stewart-Ornstein | first=Jacob | last2=Lahav | first2=Galit | title=Dynamics of CDKN1A in Single Cells Defined by an Endogenous Fluorescent Tagging Toolkit | journal=Cell Reports | publisher=Elsevier BV | volume=14 | issue=7 | year=2016 | pages=1800–1811 | url=https://doi.org/10.1016%2Fj.celrep.2016.01.045 | doi=10.1016/j.celrep.2016.01.045 | accessdate=2017-03-20}}</ref> 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;<ref name="Barr Cooper Heldt Butera 2017 p=14728">{{cite journal | last=Barr | first=Alexis R. | last2=Cooper | first2=Samuel | last3=Heldt | first3=Frank S. | last4=Butera | first4=Francesca | last5=Stoy | first5=Henriette | last6=Mansfeld | first6=Jörg | last7= Novák | first7=Béla | last8=Bakal | first8=Chris | title=DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression | journal=Nature Communications | publisher=Springer Nature | volume=8 | year=2017 | page=14728 | url=https://doi.org/10.1038%2Fncomms14728 | doi=10.1038/ncomms14728 | accessdate=2017-03-20}}</ref> this responsible for the bifurcation in CDK2 activity observed in Spencer ''et al.''.<ref name="Spencer Cappell Tsai Overton 2013 pp. 369–383" />
    | Hs_EntrezGene = 1026
 
    | Hs_Ensembl = ENSG00000124762
=== Degradation ===
    | Hs_RefseqProtein = NP_000380
 
    | Hs_RefseqmRNA = NM_000389
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 complex|SCF]]<sup>[[SKP2|Skp2]]</sup> induces degradation of p21.<ref name="Yu Gervais Zhang 1998 pp. 11324–11329">{{cite journal | last=Yu | first=Z.-K. | last2=Gervais | first2=J. L. M. | last3=Zhang | first3=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 | publisher=Proceedings of the National Academy of Sciences | volume=95 | issue=19 | year=1998 | pages=11324–11329 | url=https://doi.org/10.1073%2Fpnas.95.19.11324 | doi=10.1073/pnas.95.19.11324 | accessdate=2017-03-20| pmc=21641 }}</ref><ref name="Bornstein Bloom Sitry-Shevah Nakayama 2003 pp. 25752–25757">{{cite journal | last=Bornstein | first=G. | last2=Bloom | first2=J. | last3=Sitry-Shevah | first3=D. | last4=Nakayama | first4=K. | last5=Pagano | first5=M. | last6=Hershko | first6=A. | title=Role of the SCFSkp2 Ubiquitin Ligase in the Degradation of p21Cip1 in S Phase | journal=Journal of Biological Chemistry | publisher=American Society for Biochemistry & Molecular Biology (ASBMB) | volume=278 | issue=28 | year=2003 | pages=25752–25757 | url=https://doi.org/10.1074%2Fjbc.m301774200 | doi=10.1074/jbc.m301774200 | accessdate=2017-03-20 | pmid=12730199}}</ref> Studies have also demonstrated that the E3 ubiquitin ligase complex [[CUL4A|CRL4]]<sup>Cdt2</sup> degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication,<ref name="Kim Starostina Kipreos 2008 pp. 2507–2519">{{cite journal | last=Kim | first=Y. | last2=Starostina | first2=N. G. | last3=Kipreos | first3=E. T. | title=The CRL4Cdt2 ubiquitin ligase targets the degradation of p21Cip1 to control replication licensing | journal=Genes & Development | publisher=Cold Spring Harbor Laboratory Press | volume=22 | issue=18 | year=2008 | pages=2507–2519 | url=https://doi.org/10.1101%2Fgad.1703708 | doi=10.1101/gad.1703708 | accessdate=2017-03-20}}</ref> as well as in response to UV irradiation.<ref name="Abbas Sivaprasad Terai Amador 2008 pp. 2496–2506">{{cite journal | last=Abbas | first=T. | last2=Sivaprasad | first2=U. | last3=Terai | first3=K. | last4=Amador | first4=V. | last5=Pagano | first5=M. | last6=Dutta | first6=A. | title=PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex | journal=Genes & Development | publisher=Cold Spring Harbor Laboratory Press | volume=22 | issue=18 | year=2008 | pages=2496–2506 | url=https://doi.org/10.1101%2Fgad.1676108 | doi=10.1101/gad.1676108 | accessdate=2017-03-20 | pmid=18794347 | pmc=2546691}}</ref> Recent work has  now found that in human cell lines SCF<sup>Skp2</sup> degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4<sup>Cdt2</sup> acts to degrade p21 at a much higher rate than SCF<sup>Skp2</sup> over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase.<ref name="Barr Cooper Heldt Butera 2017 p=14728"></ref>
    | Hs_GenLoc_db = 
 
    | Hs_GenLoc_chr = 6
== Clinical significance ==
    | Hs_GenLoc_start = 36754413
 
    | Hs_GenLoc_end = 36763094
Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced [[TNM staging system|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 [[World Health Organization|WHO]] (World Health Organization) type B2/B3. When combined with low p27 and high p53, [[Disease-free survival|DFS]] (Disease-Free Survival) decreases.<ref name="Leisibach Schneiter Soltermann Yamada 2016 pp. 2580–2591">{{cite journal | last=Leisibach | first=Priska | last2=Schneiter | first2=Didier | last3=Soltermann | first3=Alex | last4=Yamada | first4=Yoshi | last5=Weder | first5=Walter | last6=Jungraithmayr | first6=Wolfgang | title=Prognostic value of immunohistochemical markers in malignant thymic epithelial tumors | journal=Journal of Thoracic Disease | publisher=AME Publishing Company | volume=8 | issue=9 | year=2016 | pages=2580–2591 | url=https://doi.org/10.21037%2Fjtd.2016.08.82 | doi=10.21037/jtd.2016.08.82 | accessdate=2017-03-20 | pmid=27747012 | pmc=5059354}}</ref>
    | Hs_Uniprot = P38936
    | Mm_EntrezGene = 12575
    | Mm_Ensembl = ENSMUSG00000023067
    | Mm_RefseqmRNA = NM_007669
    | Mm_RefseqProtein = NP_031695
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 28821439
    | Mm_GenLoc_end = 28828386
    | Mm_Uniprot = Q4FK34
  }}
}}
<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = This gene encodes a potent cyclin-dependent kinase inhibitor. The encoded protein binds to and inhibits the activity of cyclin-CDK2 or -CDK4 complexes, and thus functions as a regulator of cell cycle progression at G1. 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. This protein can 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. 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. Two alternatively spliced variants, which encode an identical protein, have been reported.<ref>{{cite web | title = Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1026| accessdate = }}</ref>
}}


{{lowercase|title=p21}}
p21 mediates the resistance of [[hematopoietic cell]]s to an infection with [[HIV]]<ref name="pmid17273559">{{cite journal | vauthors = Zhang J, Scadden DT, Crumpacker CS | title = Primitive hematopoietic cells resist HIV-1 infection via p21 | journal = J. Clin. Invest. | volume = 117 | issue = 2 | pages = 473–81  | date = February 2007 | pmid = 17273559 | pmc = 1783820 | doi = 10.1172/JCI28971 }}</ref> 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.<ref name = Chen_2011>{{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 = J. Clin. Invest. | volume = 121 | issue = 4 | pages = 1549–60  | date = April 2011 | pmid = 21403397 | doi = 10.1172/JCI44539 | laysummary = http://news.harvard.edu/gazette/story/2011/03/protein-that-helps-battle-hiv/ | laysource = Harvard Gazette | pmc=3069774}}</ref>


'''p21''', also known as '''cyclin-dependent kinase inhibitor 1A''' or '''CDKN1A''', is a human gene on [[chromosome 6]] (location 6p21.2), that encodes a [[cyclin]]-dependent [[kinase]] inhibitor that directly inhibits the activity of [[cyclin-CDK2]] and [[cyclin-CDK4]] complexes.  p21 functions as a regulator of [[cell cycle]] progression at [[G1 phase]]<ref name="Gartel2005">A. L. Gartel and S. K. Radhakrishnan (2005) "Lost in transcription: p21 repression, mechanisms, and consequences" in ''Cancer Research'' Volume 65, pages 3980-3985. {{Entrez Pubmed|15899785}}</ref>. The expression of p21 is controlled by the tumor suppressor protein [[p53]].
Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.<ref>{{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 = Res. Vet. Sci. | volume = 87 | issue = 1 | pages = 91–6 | date = August 2009 | pmid = 19185891 | doi = 10.1016/j.rvsc.2008.12.010 }}</ref><ref name=Klopfleisch>{{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 = Vet. Pathol. | volume = 48 | issue = 1 | pages = 98–116 | year = 2011 | pmid = 21149845 | doi = 10.1177/0300985810390826 }}</ref>


The function of this gene relates in part to [[Stress (medicine)|stress]] response <ref name="Rodriguez2006">R. Rodriguez and M. Meuth. (2006) "Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress" in ''Molecular Biology of the Cell'' Volume 17, pages 402-412. {{Entrez Pubmed|16280359}}</ref>.
Mice that lack the p21 gene gain the ability to [[Regeneration (biology)|regenerate]] lost appendages.<ref name="Heber-Katz_2010">{{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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 13 | pages = 5845–50  | date = March 2010 | pmid = 20231440 | pmc = 2851923 | doi = 10.1073/pnas.1000830107 | url = http://www.pnas.org/content/early/2010/03/08/1000830107.abstract | laysummary = http://www.physorg.com/news187879295.html | laysource = PhysOrg.com }}</ref>


p21 is also mediating the resistance of [[hematopoietic cell]]s to an infection with [[HIV]] <ref name="Zhang et al., 2007">Zhang J, Scadden DT, Crumpacker CS.: Primitive hematopoietic cells resist HIV-1 infection via p21. J Clin Invest. 2007 Feb 1;117(2):473-481. PMID 17273559 </ref> by complexing with the HIV integrase and thereby aborting chromosomal integration of the [[provirus]].
== Interactions ==


==External links==
{{div col|colwidth=25em}}
* {{MeshName|Cyclin-Dependent+Kinase+Inhibitor+p21}}
P21 has been shown to [[Protein-protein interaction|interact]] with:
* [[Nrf2]]<ref name=pmid19560419>{{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 = Mol. Cell | volume = 34 | issue = 6 | pages = 663–73  | date = June 2009 | pmid = 19560419 | pmc = 2714804 | doi = 10.1016/j.molcel.2009.04.029 }}</ref>
* [[BCCIP]],<ref name=pmid10878006/>
* [[CIZ1]],<ref name="pmid10529385">{{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 = Biochem. Biophys. Res. Commun. | volume = 264 | issue = 2 | pages = 457–64  | date = October 1999 | pmid = 10529385 | doi = 10.1006/bbrc.1999.1516 }}</ref>
* [[CUL4A]],<ref name="pmid18794347">{{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 Dev. | volume = 22 | issue = 18 | pages = 2496–506  | date = September 2008 | pmid = 18794347 | pmc = 2546691 | doi = 10.1101/gad.1676108 }}</ref>
* [[Cyclin E1|CCNE1]],<ref name=pmid12839982/>
* [[Cyclin-dependent kinase 2|CDK]],<ref name="pmid8242751"/><ref name="pmid10878006">{{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 = J. Biol. Chem. | volume = 275 | issue = 40 | pages = 31145–54  | date = October 2000 | pmid = 10878006 | doi = 10.1074/jbc.M003031200 }}</ref><ref name="pmid12839982">{{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 Res. | volume = 63 | issue = 13 | pages = 3840–4  | date = July 2003 | pmid = 12839982 | doi =  }}</ref><ref name="pmid12417722">{{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 = Mol. Cell. Biol. | volume = 22 | issue = 23 | pages = 8184–98  | date = December 2002 | pmid = 12417722 | pmc = 134072 | doi = 10.1128/MCB.22.23.8184-8198.2002 }}</ref><ref name="pmid9858587">{{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 = Mol. Cell. Biol. | volume = 19 | issue = 1 | pages = 635–45  | date = January 1999 | pmid = 9858587 | pmc = 83921 | doi =  10.1128/mcb.19.1.635}}</ref>
* [[DDB1]],<ref name=pmid18794347/>
* [[DTL (gene)|DTL]],<ref name=pmid18794347/>
* [[GADD45A]],<ref name="pmid10912791">{{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 = Exp. Cell Res. | volume = 258 | issue = 1 | pages = 92–100  | date = July 2000 | pmid = 10912791 | doi = 10.1006/excr.2000.4906 }}</ref><ref name="pmid10973963">{{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 = J. Biol. Chem. | volume = 275 | issue = 47 | pages = 36892–8  | date = November 2000 | pmid = 10973963 | doi = 10.1074/jbc.M005319200 }}</ref>
* [[GADD45G]],<ref name="pmid11022036">{{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 = J. Biol. Chem. | volume = 276 | issue = 4 | pages = 2766–74  | date = January 2001 | pmid = 11022036 | doi = 10.1074/jbc.M005626200 }}</ref><ref name="pmid10455148">{{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 = J. Biol. Chem. | volume = 274 | issue = 35 | pages = 24766–72  | date = August 1999 | pmid = 10455148 | doi = 10.1074/jbc.274.35.24766 }}</ref>
* [[Histone_deacetylase|HDAC]],<ref>{{cite journal |last1=Zupkovitz |first1=Gordin |last2=Lagger |first2=Sabine |last3=Martin |first3=David |last4=Steiner |first4=Marianne |last5=Hagelkruys |first5=Astrid |last6=Seiser |first6=Christian |last7=Schöfer |first7=Christian |last8=Pusch |first8=Oliver |title=Histone deacetylase 1 expression is inversely correlated with age in the short-lived fish Nothobranchius furzeri |journal=Histochemistry and Cell Biology |date=28 June 2018 |volume=150 |issue=3 |pages=255–269 |doi= 10.1007/s00418-018-1687-4}}</ref>
* [[PCNA]],<ref name="pmid16189514">{{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 = 1173–8  | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}</ref><ref name="pmid12930846">{{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 = J. Biol. Chem. | volume = 278 | issue = 41 | pages = 39265–8  | date = October 2003 | pmid = 12930846 | doi = 10.1074/jbc.C300098200 }}</ref><ref name="pmid9465025">{{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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 4 | pages = 1392–7  | date = February 1998 | pmid = 9465025 | pmc = 19016 | doi = 10.1073/pnas.95.4.1392 }}</ref><ref name="pmid8861969">{{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 = EMBO J. | volume = 15 | issue = 16 | pages = 4423–33  | date = August 1996 | pmid = 8861969 | pmc = 452166 | doi =  }}</ref><ref name="pmid9545252">{{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 = EMBO J. | volume = 17 | issue = 8 | pages = 2412–25  | date = April 1998 | pmid = 9545252 | pmc = 1170584 | doi = 10.1093/emboj/17.8.2412 }}</ref><ref name="pmid8861913">{{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 }}</ref><ref name="pmid11350925">{{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 = EMBO J. | volume = 20 | issue = 10 | pages = 2367–75  | date = May 2001 | pmid = 11350925 | pmc = 125454 | doi = 10.1093/emboj/20.10.2367 }}</ref><ref name="pmid11313979">{{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 = 484–9  | date = January 2001 | pmid = 11313979 | doi = 10.1038/sj.onc.1204113 }}</ref>
* [[PIM1]],<ref name="pmid12431783">{{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 = Biochim. Biophys. Acta | volume = 1593 | issue = 1 | pages = 45–55  | date = December 2002 | pmid = 12431783 | doi = 10.1016/S0167-4889(02)00347-6 }}</ref>
* [[Thymidine kinase 1|TK1]],<ref name="pmid11389691">{{cite journal | vauthors = Huang DY, Chang ZF | title = Interaction of human thymidine kinase 1 with p21(Waf1) | journal = Biochem. J. | volume = 356 | issue = Pt 3 | pages = 829–34  | date = June 2001 | pmid = 11389691 | pmc = 1221910 | doi = 10.1042/0264-6021:3560829 }}</ref> and
* [[TSG101]].<ref name="pmid11943869">{{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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 8 | pages = 5430–5  | date = April 2002 | pmid = 11943869 | pmc = 122786 | doi = 10.1073/pnas.082123999 }}</ref>
{{Div col end}}


==References==
== References ==
{{reflist|2}}
{{Reflist|2}}
<div class="references-small">{{reflist|2}}</div>


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Marone M, Bonanno G, Rutella S, Leone G, Scambia G, Pierelli L | title = Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21 | journal = Leuk. Lymphoma | volume = 43 | issue = 1 | pages = 51–7 | year = 2002 | pmid = 11908736 | doi = 10.1080/10428190210195 }}
| citations =
* {{cite journal | vauthors = Fang JY, Lu YY | title = Effects of histone acetylation and DNA methylation on p21( WAF1) regulation | journal = World J. Gastroenterol. | volume = 8 | issue = 3 | pages = 400–5 | year = 2002 | pmid = 12046058 | doi =  }}
*{{cite journal | author=Marone M, Bonanno G, Rutella S, ''et al.'' |title=Survival and cell cycle control in early hematopoiesis: role of bcl-2, and the cyclin dependent kinase inhibitors P27 and P21. |journal=Leuk. Lymphoma |volume=43 |issue= 1 |pages= 51-7 |year= 2003 |pmid= 11908736 |doi= }}
* {{cite journal | vauthors = Tokumoto M, Tsuruya K, Fukuda K, Kanai H, Kuroki S, Hirakata H, Iida M | title = Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27 | journal = Nephrol. Dial. Transplant. | volume = 18 Suppl 3 | issue =  | pages = iii9-12 | year = 2003 | pmid = 12771291 | doi =  10.1093/ndt/gfg1003}}
*{{cite journal | author=Fang JY, Lu YY |title=Effects of histone acetylation and DNA methylation on p21( WAF1) regulation. |journal=World J. Gastroenterol. |volume=8 |issue= 3 |pages= 400-5 |year= 2002 |pmid= 12046058 |doi=  }}
* {{cite journal | vauthors = Amini S, Khalili K, Sawaya BE | title = Effect of HIV-1 Vpr on cell cycle regulators | journal = DNA Cell Biol. | volume = 23 | issue = 4 | pages = 249–60 | year = 2004 | pmid = 15142382 | doi = 10.1089/104454904773819833 }}
*{{cite journal | author=Tokumoto M, Tsuruya K, Fukuda K, ''et al.'' |title=Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor and cyclin-dependent kinase inhibitors, p21 and p27. |journal=Nephrol. Dial. Transplant. |volume=18 Suppl 3 |issue=  |pages= iii9-12 |year= 2003 |pmid= 12771291 |doi=  }}
* {{cite journal | vauthors = Zhang Z, Wang H, Li M, Rayburn E, Agrawal S, Zhang R | title = Novel MDM2 p53-independent functions identified through RNA silencing technologies | journal = Ann. N. Y. Acad. Sci. | volume = 1058 | issue =  | pages = 205–14 | year = 2005 | pmid = 16394138 | doi = 10.1196/annals.1359.030 }}
*{{cite journal | author=Amini S, Khalili K, Sawaya BE |title=Effect of HIV-1 Vpr on cell cycle regulators. |journal=DNA Cell Biol. |volume=23 |issue= 4 |pages= 249-60 |year= 2004 |pmid= 15142382 |doi= 10.1089/104454904773819833 }}
*{{Cite journal
*{{cite journal | author=Zhang Z, Wang H, Li M, ''et al.'' |title=Novel MDM2 p53-independent functions identified through RNA silencing technologies. |journal=Ann. N. Y. Acad. Sci. |volume=1058 |issue=  |pages= 205-14 |year= 2006 |pmid= 16394138 |doi= 10.1196/annals.1359.030 }}
|author1=P. Sankaranarayanan |author2=T. E. Schomay |author3=K. A. Aiello |author4=O. Alter | title = 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
| journal = PLOS ONE
| volume = 10
| issue = 4
| pages = e0121396
| date = April 2015
| doi = 10.1371/journal.pone.0121396
| url = https://dx.doi.org/10.1371/journal.pone.0121396
| id = [http://www.eurekalert.org/pub_releases/2015-04/uouh-nmi040915.php AAAS EurekAlert! Press Release] and [https://www.nae.edu/Projects/20730/wtop/134897.aspx NAE Podcast Feature]
| pmid=25875127
| pmc=4398562
}}
}}
{{refend}}
{{refend}}


== 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}}


{{Tumor suppressor genes}}
{{Tumor suppressor genes}}
{{Cell cycle proteins}}
{{Cell cycle proteins}}
{{Protein-stub}}
 
[[Category:Genes]]
[[Category:Cell cycle]]
[[Category:Cell cycle]]
[[de:P21]]
[[pl:P21]]
[[pt:P21]]
{{WikiDoc Sources}}

Latest revision as of 23:50, 13 November 2018

This article is about the p21Cip1 protein. For the p21/ras protein, see Ras (protein). For other uses, see P21 (disambiguation).

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p21Cip1 (alternatively p21Waf1), 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,[1] though is primarily associated with inhibition of CDK2.[2][3] p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest.[4][5][6] This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.[7]

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.[8][9] 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.[2] 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.[10]

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.[11] 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.[12]

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.[13][14][15] Specifically, p21 has a high affinity for the PIP-box binding region on PCNA,[16] 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).[17] As such, p21 acts as an effective inhibitor of DNA 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.[18]

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.[19] The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported.[20]

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.[21] 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.[22] 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.[23][9] 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.[24] 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;[25] this responsible for the bifurcation in CDK2 activity observed in Spencer et al..[11]

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 SCFSkp2 induces degradation of p21.[26][27] Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4Cdt2 degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication,[28] as well as in response to UV irradiation.[29] Recent work has now found that in human cell lines SCFSkp2 degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4Cdt2 acts to degrade p21 at a much higher rate than SCFSkp2 over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase.[25]

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.[30]

p21 mediates the resistance of hematopoietic cells to an infection with HIV[31] 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.[32]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.[33][34]

Mice that lack the p21 gene gain the ability to regenerate lost appendages.[35]

Interactions

P21 has been shown to interact with:

References

  1. ↑ Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993). "p21 is a universal inhibitor of cyclin kinases". Nature. 366: 701–4. doi:10.1038/366701a0. PMID 8259214.
  2. ↑ 2.0 2.1 Abbas, Tarek; Dutta, Anindya (2009). "p21 in cancer: intricate networks and multiple activities". Nature Reviews Cancer. Springer Nature. 9 (6): 400–414. doi:10.1038/nrc2657. PMC 2722839. Retrieved 2017-03-20.
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Further reading

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