P21

This article is about the p21^Cip1 protein. For the p21/ras protein, see Ras (protein). For other uses, see P21 (disambiguation).

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; OMA:CDKN1A - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p21.2 Start 36,676,460 bp[1] End 36,687,339 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 A3.3|17 15.12 cM Start 29,309,950 bp[2] End 29,319,701 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium gastric mucosa vena cava left uterine tube beta cell ascending aorta saphenous vein popliteal artery tibial arteries Descending thoracic aorta Top expressed in stroma of bone marrow calvaria molar pyloric antrum lip esophagus hair follicle epithelium of stomach skin of external ear endothelial cell of lymphatic vessel More reference expression data BioGPS More reference expression data
Gene ontology Molecular function 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 cyclin-dependent protein serine/threonine kinase activity protein kinase inhibitor activity protein kinase binding protein-containing complex binding Cellular component cytoplasm cytosol cyclin-dependent protein kinase holoenzyme complex PCNA-p21 complex perinuclear region of cytoplasm nucleus nucleoplasm nucleolus nuclear body protein-containing complex 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 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 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 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 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 negative regulation of cell population proliferation protein stabilization positive regulation of cyclin-dependent protein kinase activity regulation of transcription by RNA polymerase II DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator positive regulation of protein kinase activity cellular response to gamma radiation negative regulation of cyclin-dependent protein kinase activity transcription initiation from RNA polymerase II promoter G1/S transition of mitotic cell cycle cytokine-mediated signaling pathway negative regulation of vascular associated smooth muscle cell proliferation Sources:Amigo / QuickGO
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 NP_001207706 NP_001207707 NP_001278478 NP_510867 NP_001361438 NP_001361439 NP_001361440 NP_001361441 NP_001361442 NP_001104569 NP_031695 Location (UCSC) Chr 6: 36.68 – 36.69 Mb Chr 17: 29.31 – 29.32 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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,^[5] though is primarily associated with inhibition of CDK2.^[6][7] p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest.^[8][9][10] This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.^[11]

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.^[12][13] 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.^[6] 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.^[14]

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.^[15] 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.^[16]

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.^[17][18][19] Specifically, p21 has a high affinity for the PIP-box binding region on PCNA,^[20] 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).^[21] 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.^[22]

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.^[23] The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported.^[24]

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.^[25] 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.^[26] 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.^[27][13] 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.^[28] 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;^[29] this responsible for the bifurcation in CDK2 activity observed in Spencer et al..^[15]

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.^[30][31] 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,^[32] as well as in response to UV irradiation.^[33] 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.^[29]

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.^[34]

p21 mediates the resistance of hematopoietic cells to an infection with HIV^[35] 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.^[36]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.^[37][38]

Mice that lack the p21 gene gain the ability to regenerate lost appendages.^[39]

Interactions

P21 has been shown to interact with:

• Nrf2^[40]
• BCCIP,^[41]
• CIZ1,^[42]
• CUL4A,^[43]
• CCNE1,^[44]
• CDK,^{[7][41][44][45][46]}
• DDB1,^[43]
• DTL,^[43]
• GADD45A,^[47][48]
• GADD45G,^[49][50]
• HDAC,^[51]
• PCNA,^{[52][53][54][55][56][57][58][59]}
• PIM1,^[60]
• TK1,^[61] and
• TSG101.^[62]

References

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58. 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. S2CID 28490341.
• Fang JY, Lu YY (2002). "Effects of histone acetylation and DNA methylation on p21( WAF1) regulation". World J. Gastroenterol. 8 (3): 400–5. doi:10.3748/wjg.v8.i3.400. PMC 4656409. 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 (90003): 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 (1): 205–14. Bibcode:2005NYASA1058..205Z. doi:10.1196/annals.1359.030. PMID 16394138. S2CID 35683657.
• P. Sankaranarayanan; T. E. Schomay; K. A. Aiello; 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. Bibcode:2015PLoSO..1021396S. 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 U.S. 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.
• Overview of all the structural information available in the PDB for UniProt: P38936 (Human Cyclin-dependent kinase inhibitor 1) at the PDBe-KB.