Contents 1 Nomenclature 2 Gene 3 Function 4 Regulation 5 Clinical significance 5.1 Role in cancer 6 Clinical use 6.1 Use as a biomarker 6.2 p16 FISH 6.3 p16 immunochemistry 6.3.1 gynecologic cancers 6.4 Urinary bladder SCCs 6.5 Role in senescence 7 Experimental analysis of p16 mutation 8 Discovery 9 Interactions 10 See also 11 References 12 External links

Nomenclature[edit] p16 is also known as: p16Ink4A p16Ink4 Cyclin-dependent kinase inhibitor 2A (CDKN2A) CDKN2 CDK 4 Inhibitor Multiple Tumor Suppressor 1 (MTS1) TP16 ARF MLM P14 P19

Gene[edit] In humans, p16 is encoded by the CDKN2A gene, located on chromosome 9 (9p21.3). This gene generates several transcript variants that differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4. The remaining transcript includes an alternate exon 1 located 20 kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein that is structurally unrelated to the products of the other variants.[5] The ARF product functions as a stabilizer of the tumor suppressor protein p53, as it can interact with and sequester MDM2, a protein responsible for the degradation of p53.[6][7] In spite of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in control of the G1 phase of the cell cycle. This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene.[1] Increased expression of the p16 gene as organisms age reduces the proliferation of stem cells.[8] This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.

Function[edit] p16 is a cyclin-dependent kinase (CDK) inhibitor that slows down the cell cycle by prohibiting progression from G1 phase to S phase. Normally, CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB). Once phosphorylated, pRB disassociates from the transcription factor E2F1, liberating E2F1 from its cytoplasm bound state allowing it to enter the nucleus. Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.[9][10] p16 acts as a tumor suppressor by binding to CDK4/6 and preventing its interaction with cyclin D. This interaction ultimately inhibits the downstream activities of transcription factors, such as E2F1, and arrests cell proliferation.[10] This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum. On one end, the hypermethylation, mutation, or deletion of p16 leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression. Conversely, activation of p16 through the ROS pathway, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in aging of cells.[9]

Regulation[edit] Regulation of p16 is complex and involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region.[9] PRC1 and PRC2 are two protein complexes that modify the expression of p16 through the interaction of various transcription factors that execute methylation patterns that can repress transcription of p16. These pathways are activated in cellular response to reduce senescence.[11][12]

Clinical significance[edit] Role in cancer[edit] Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers and alterations of the gene are frequently seen in cancer cell lines.[13][14] Examples include: Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene.[15][16][17] Carriers of germline mutations in CDKN2A have besides their high risks of melanoma also increased risks of pancreatic, lung, laryngeal and oropharyngeal cancers and tobacco smoking exacerbates carriers’ susceptibility for such non-melanoma cancers.[18] Homozygous deletion of p16 are frequently found in esophageal cancer and gastric cancer cell lines.[19] Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer.[20] Hypermethylation of tumor suppressor genes has been implicated in various cancers. In 2013, a meta-analysis of 39 articles using analysis cancer tissues and 7 articles using blood samples, revealed an increased frequency of DNA methylation of p16 gene in esophageal cancer. As the degree of tumor differentiation increased, so did the frequency of DNA methylation. Tissue samples of primary oral squamous cell carcinoma (OSCC) display hypermethylation in the promoter regions of p16. Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16. This epigenetic change leads to the loss of tumor suppressor gene function through two possible mechanisms. Methylation can physically inhibit the transcription of the gene or methylation can lead to the recruitment of transcription factors that repress transcription. Both mechanisms lead to the same end result—downregulation of gene expression that leads to decreased levels of the p16 protein. It has been suggested that this process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.[21][22][23][24][25][26] Using p16 as a surrogate marker of HPV status in oral cavity dysplasia and OSCC is discouraged. HPV-driven OSCC has a very low incidence. Studies have shown that up to a third of OSCC are p16 positive and viral DNA is detectable by polymerase chain reaction in up to 28% of cases [51,52]. However when studies use in situ hybridization, a more sensitive method of detecting high-risk HPV, very few cases (1–10%) are positive [51–56]. Therefore, relying on p16 as a surrogate marker for HPV overestimates the number of HPV-related cancers in the oral cavity. In addition, studies have shown no survival benefit in p16 positive OSCC compared to p16 negative OSCC.(51,52)

Clinical use[edit] Use as a biomarker[edit] Furthermore, p16 is now being explored as a prognostic biomarker for a number of cancers. For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course. Presence of the biomarker is associated with a more favorable prognosis as measured by cancer-specific survival (CSS), recurrence-free survival (RFS), locoregional control (LRC), as well as other measurements. The appearance of hyper methylation of p16 is also being evaluated as a potential prognostic biomarker for prostate cancer.[27][28][29] p16 FISH[edit] p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.[30] p16 immunochemistry[edit] High grade squamous intraepithelial lesion showing strong p16 staining. gynecologic cancers[edit] p16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin. The majority of SCCs of uterine cervix express p16. However, p16 can be expressed in other neoplasms and in several normal human tissues.[31] Urinary bladder SCCs[edit] More than a third of urinary bladder SCCs express p16. SCCs of urinary bladder express p16 independent of gender. p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.[31] Role in senescence[edit] Concentrations of p16INK4a increase dramatically as tissue ages. p16INK4a, along with senescence-associated beta-galactosidase, is regarded to be a biomarker of cellular senescence.[32] Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.[33] Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify p16 as belonging to a "core signature" of senescence markers.[34] It has been used as a target to delay some aging changes in mice.[35]

Experimental analysis of p16 mutation[edit] As consensus grows regarding the strength of p16 as a biomarker for detecting and determining prognoses of cancer, p16 immunohistochemistry is growing in importance.[9][27][36]

Discovery[edit] Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor. Since its discovery, p16 has become significant in the field of cancer research. The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines. The detection of p16 inactivation in familial melanoma supplied further evidence. p16 deletion, mutation, or hypermethylation is now associated with various cancers. Whether p16 can be considered to be a driver mutation requires further investigation.[13]

Interactions[edit] P16 (gene) has been shown to interact with: CCNG1,[37] CDK4,[4][38][39][40][41][42] CDK6,[41][43][44] DAXX,[45] E4F1,[46] MDM2,[45][47][48][49][50] P53,[46][47][48] PPP1R9B,[51] RPL11,[47] and SERTAD1.[38][39]

See also[edit] p21 p53 Cyclin-dependent kinase Cyclin D

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External links[edit] Genes, p16 at the US National Library of Medicine Medical Subject Headings (MeSH) CDKN2A human gene location in the UCSC Genome Browser. CDKN2A human gene details in the UCSC Genome Browser. v t e PDB gallery 1a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 18 STRUCTURES  1bi7: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX  1dc2: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 20 STRUCTURES  2a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, RESTRAINED MINIMIZED MEAN STRUCTURE  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 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 Retrieved from "" Categories: Tumor suppressor genes

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P16 - Photos and All Basic Informations

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P16 (disambiguation)PfamInterProStructural Classification Of ProteinsSUPERFAMILYPfamProtein Data BankPDBsumTumor Suppressor GeneProteinCDKN2AGeneCell CycleG1 PhaseS PhaseCancersMelanomaOropharyngeal CancerCervical CancerEsophageal CancerCIN3Ankyrin RepeatCDKN2AChromosome 9 (human)GeneTranscription (genetics)ExonSplicing (genetics)Protein IsoformEnzyme InhibitorCyclin-dependent Kinase 4KilobaseP14arfP53 (protein)MDM2Cell CycleStem CellCancerSenescenceRetinoblastoma ProteinE2F1Cell LinePancreatic CancerEsophageal CancerGastric CancerSkin CancerEpigeneticDeletion (genetics)FISH (genetic)MesotheliomaEnlargeSquamous Cell CarcinomaHuman Papilloma VirusSenescence-associated Beta-galactosidaseBiomarkerSenescenceProtein-protein InteractionCCNG1Cyclin-dependent Kinase 4Cyclin-dependent Kinase 6Death Associated Protein 6E4F1Mdm2P53PPP1R9BRPL11SERTAD1P21P53Cyclin-dependent KinaseCyclin DDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierInternational Standard Book NumberSpecial:BookSources/978-0-19-926472-8Digital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierAging (journal)Digital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed CentralPubMed IdentifierDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierCarlos Cordon-CardoDigital Object IdentifierPubMed IdentifierDigital Object IdentifierPubMed IdentifierMedical Subject HeadingsUCSC Genome BrowserUCSC Genome BrowserTemplate:PDB GalleryTemplate Talk:PDB Gallery1a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 18 STRUCTURES1bi7: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX1dc2: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 20 STRUCTURES2a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, RESTRAINED MINIMIZED MEAN STRUCTURETemplate: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 CycleP14arfCDKN2BCDKN2CCDKN2DCell CycleP21CDKN1BCyclin-dependent Kinase Inhibitor 1CP53 P63 P73 FamilyP53TP63P73Cdk1Cdc25CDC42Cellular Apoptosis Susceptibility ProteinE2FMaturation Promoting FactorWee1CullinCUL7InterphaseG1 PhaseS PhaseG2 PhaseCell DivisionMitosisPreprophaseProphasePrometaphaseMetaphaseAnaphaseTelophaseCytokinesisCell Cycle CheckpointRestriction PointSpindle CheckpointPostreplication CheckpointApoptosisG0 PhaseMeiosisTemplate: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 SignalingStathminHelp:CategoryCategory:Tumor Suppressor GenesDiscussion About Edits From This IP Address [n]A List Of Edits Made From This IP Address [y]View The Content Page [c]Discussion 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