Contents 1 Function 1.1 CDK inhibition 1.2 PCNA inhibition 1.3 Apoptosis inhibition 2 Regulation 2.1 p53 dependent response 2.2 Degradation 3 Clinical significance 4 Interactions 5 References 6 Further reading 7 External links

Function[edit] CDK inhibition[edit] 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, were CDK2 inhibits p21 activity via ubiquitin ligase activity.[16] PCNA inhibition[edit] 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 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.[22] Apoptosis inhibition[edit] 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 inihbit apoptosis in response to replication fork stress has also been reported.[24]

Regulation[edit] p53 dependent response[edit] 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] 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.[30] Degradation[edit] 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.[31][32] 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,[33] as well as in response to UV irradiation.[34] 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.[29]

Clinical significance[edit] 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.[35] p21 mediates the resistance of hematopoietic cells to an infection with HIV[36] 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.[37] Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation.[38][39] Mice that lack the p21 gene gain the ability to regenerate lost appendages.[40]

Interactions[edit] P21 has been shown to interact with: Nrf2[41] BCCIP,[42] CIZ1,[43] CUL4A,[44] CCNE1,[45] CDK,[7][42][45][46][47] DDB1,[44] DTL,[44] GADD45A,[48][49] GADD45G,[50][51] PCNA,[52][53][54][55][56][57][58][59] PIM1,[60] TK1,[61] and TSG101.[62]

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Further reading[edit] 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; 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[edit] 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. v t e Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes Ligand Growth factors ONCO c-Sis/PDGF HGF Receptor Wnt signaling pathway TSP CDH1 Hedgehog signaling pathway TSP PTCH1 TGF beta signaling pathway TSP TGF beta receptor 2 Receptor tyrosine kinase ONCO ErbB/c-ErbB HER2/neu Her 3 c-Met c-Ret JAK-STAT signaling pathway ONCO c-Kit Flt3 Intracellular signaling P+Ps Wnt signaling pathway ONCO Beta-catenin TSP APC TGF beta signaling pathway TSP SMAD2 SMAD4 Akt/PKB signaling pathway ONCO c-Akt TSP PTEN Hippo signaling pathway TSP Neurofibromin 2/Merlin MAPK/ERK pathway ONCO c-Ras HRAS c-Raf TSP Neurofibromin 1 Other/unknown ONCO c-Src TSP Maspin Nucleus Cell cycle ONCO CDK4 Cyclin D Cyclin E TSP p53 pRb WT1 p16/p14arf DNA repair/Fanconi TSP BRCA1 BRCA2 Ubiquitin ligase ONCO CBL MDM2 TSP VHL Transcription factor ONCO AP-1 c-Fos c-Jun c-Myc TSP KLF6 Mitochondrion Apoptosis inhibitor SDHB SDHD Other/ungrouped c-Bcl-2 Notch Stathmin v t e Cell cycle proteins Cyclin A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2) CDK 1 2 3 4 5 6 7 8 9 10 CDK-activating kinase CDK inhibitor INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57) P53 p63 p73 family p53 p63 p73 Other Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin (CUL7) Phases and checkpoints Interphase G1 phase S phase G2 phase M phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G0 phase Meiosis Retrieved from "" Categories: Genes on human chromosome 6Human genesCell cycle

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P21 - Photos and All Basic Informations

P21 More Links

Ras (protein)P21 (disambiguation)Protein Data BankGene NomenclatureMendelian Inheritance In ManMouse Genome InformaticsHomoloGeneGeneCardsChromosome 6 (human)ChromosomeChromosome 6 (human)Chromosome 6 (human)Genomic Location For CDKN1AGenomic Location For CDKN1ALocus (genetics)Base PairBase PairChromosome 17 (mouse)ChromosomeChromosome 17 (mouse)Genomic Location For CDKN1AGenomic Location For CDKN1ALocus (genetics)Base PairBase PairGene ExpressionGene OntologyEntrezEnsemblUniProtPubMedWikidataCyclin-dependent Kinase InhibitorCDK2TP53GeneChromosome 6Cyclin-dependent Kinase InhibitorCyclinCyclin-dependent Kinase 2Cyclin-dependent Kinase 1Cyclin-dependent Kinase 4Cyclin-dependent Kinase 6Cell CycleCell Cycle CheckpointS PhaseP27 (gene)P57 (gene)G0 PhaseUbiquitin LigasePCNANucleotide Excision RepairCASP3CaspaseApoptosisCaspaseCyclin ECDK2Ubiquitin LigasesSCF ComplexSKP2CUL4ATNM Staging SystemOverall Survival RateWorld Health OrganizationDisease-free SurvivalHematopoietic CellHIVProvirusRegeneration (biology)Protein-protein InteractionNrf2BCCIPCIZ1CUL4ACyclin E1Cyclin-dependent Kinase 2DDB1DTL (gene)GADD45AGADD45GPCNAPIM1Thymidine Kinase 1TSG101Ensembl Genome Database ProjectEnsembl Genome Database ProjectDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierMedical Subject HeadingsUCSC Genome BrowserUCSC Genome BrowserTemplate:Tumor Suppressor Genes And OncogenesTemplate Talk:Tumor Suppressor Genes And OncogenesNeoplasmTumor Suppressor GeneOncogeneLigand (biochemistry)Growth FactorPlatelet-derived Growth FactorHepatocyte Growth FactorReceptor (biochemistry)Wnt Signaling PathwayCDH1 (gene)Hedgehog Signaling PathwayPTCH1TGF Beta Signaling PathwayTGF Beta Receptor 2Receptor Tyrosine KinaseErbBEpidermal Growth Factor ReceptorHER2/neuERBB3C-MetRET Proto-oncogeneJAK-STAT Signaling PathwayCD117CD135Intracellular Signaling Peptides And ProteinsWnt Signaling PathwayBeta-cateninAdenomatosis Polyposis ColiTGF Beta Signaling PathwayMothers Against Decapentaplegic Homolog 2Mothers Against Decapentaplegic Homolog 4Akt/PKB Signaling PathwayAKTPTEN (gene)Hippo Signaling PathwayMerlin (protein)MAPK/ERK PathwayRas (protein)HRASC-RafNeurofibromin 1Proto-oncogene Tyrosine-protein Kinase SrcMaspinCell NucleusCell CycleCyclin-dependent Kinase 4Cyclin DCyclin EP53Retinoblastoma ProteinWT1P16 (gene)P14arfDNA RepairFanconi AnemiaBRCA1BRCA2Ubiquitin LigaseCBL (gene)Mdm2Von Hippel–Lindau Tumor SuppressorTranscription FactorAP-1 Transcription FactorC-FosC-junMycKLF6MitochondrionInhibitor Of ApoptosisSDHBSDHDBcl-2Notch SignalingStathminTemplate:Cell Cycle ProteinsTemplate Talk:Cell Cycle ProteinsCell CycleProteinCyclinCyclin ACyclin A1Cyclin A2Cyclin BCyclin B1Cyclin B2Cyclin DCyclin D1Cyclin D2Cyclin D3Cyclin ECyclin E1Cyclin E2Cyclin-dependent KinaseCyclin-dependent Kinase 1Cyclin-dependent Kinase 2Cyclin-dependent Kinase 3Cyclin-dependent Kinase 4Cyclin-dependent Kinase 5Cyclin-dependent Kinase 6Cyclin-dependent Kinase 7Cyclin-dependent Kinase 8Cyclin-dependent Kinase 9Cyclin-dependent Kinase 10CDK-activating KinaseCyclin-dependent Kinase Inhibitor ProteinCell CycleP14arfP16CDKN2BCDKN2CCDKN2DCell CycleCDKN1BCyclin-dependent Kinase Inhibitor 1CP53 P63 P73 FamilyP53TP63P73Cdk1Cdc25CDC42Cellular Apoptosis Susceptibility ProteinE2FMaturation Promoting FactorWee1CullinCUL7InterphaseG1 PhaseS PhaseG2 PhaseCell DivisionMitosisPreprophaseProphasePrometaphaseMetaphaseAnaphaseTelophaseCytokinesisCell Cycle CheckpointRestriction 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