Summary: Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus
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P16 (gene) Edit Wikipedia article
|Cyclin-dependent kinase inhibitor 2A|
PDB rendering based on 1a5e.
|RNA expression pattern|
|Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus|
solution structure of the n-terminal 37 amino acids of the mouse arf tumor suppressor protein
p16 (also known as cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 and as several other synonyms), is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene. p16 plays an important role in cell cycle regulation by decelerating cells progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, and esophageal cancer. The CDKN2A gene is frequently mutated or deleted in a wide variety of tumors.
p16 is an inhibitor of cyclin dependent kinases such as CDK4 and CDK6. These latter kinases phosphorylate retinoblastoma protein (pRB) which eventually results in progression from G1 phase to S phase.
p16 was originally found in an âopen reading frame of 148 amino acids encoding a protein of molecular weight 15,845 comprising four ankyrin repeats.â p16Ink4A is named after its molecular weight and its role in inhibiting CDK4.
p16 is also known as:
- Cyclin-dependent kinase inhibitor 2A (CDKN2A)
- CDK 4 Inhibitor
- Multiple Tumor Suppressor 1 (MTS1)
In humans, p16 is encoded by 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. 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. 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.
Increased expression of the p16 gene as organisms age reduces the proliferation of stem cells. This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.
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.
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. 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 build up of p16 in tissues and is implicated in aging of cells.
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.
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.
Role in cancer
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.
Use as a biomarker
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.
Role in senescence
Concentrations of p16INK4a increase dramatically as tissue ages. Therefore p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.
Experimental analysis of p16 mutation
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.
P16 (gene) has been shown to interact with:
- "Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)".
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- Hara E, Smith R, Parry D, Tahara H, Stone S, Peters G (March 1996). "Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence". Mol. Cell. Biol. 16 (3): 859â67. PMC 231066. PMID 8622687.
- Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, Jones RS, Zhang Y (November 2002). "Role of histone H3 lysine 27 methylation in Polycomb-group silencing". Science 298 (5595): 1039â43. doi:10.1126/science.1076997. PMID 12351676.
- Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-MÃ¶nch K, Minucci S, Porse BT, Marine JC, Hansen KH, Helin K (March 2007). "The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells". Genes Dev. 21 (5): 525â30. doi:10.1101/gad.415507. PMC 1820894. PMID 17344414.
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- Bartsch D, Shevlin DW, Tung WS, Kisker O, Wells SA, Goodfellow PJ (November 1995). "Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas". Genes Chromosomes Cancer 14 (3): 189â95. doi:10.1002/gcc.2870140306. PMID 8589035.
- Liu L, Lassam NJ, Slingerland JM, Bailey D, Cole D, Jenkins R, Hogg D (July 1995). "Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma". Oncogene 11 (2): 405â12. PMID 7624155.
- Igaki H, Sasaki H, Kishi T, Sakamoto H, Tachimori Y, Kato H, Watanabe H, Sugimura T, Terada M (September 1994). "Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines". Biochem. Biophys. Res. Commun. 203 (2): 1090â5. doi:10.1006/bbrc.1994.2294. PMID 8093026.
- Khor GH, Froemming GR, Zain RB, Abraham MT, Omar E, Tan SK, Tan AC, Vincent-Chong VK, Thong KL (2013). "DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma". Int J Med Sci 10 (12): 1727â39. doi:10.7150/ijms.6884. PMC 3805925. PMID 24155659.
- Demokan S, Chuang A, SuoÄlu Y, Ulusan M, YalnÄ±z Z, Califano JA, Dalay N (October 2012). "Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer". Head Neck 34 (10): 1470â5. doi:10.1002/hed.21949. PMID 22106032.
- Shaw RJ, Liloglou T, Rogers SN, Brown JS, Vaughan ED, Lowe D, Field JK, Risk JM (February 2006). "Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: quantitative evaluation using pyrosequencing". Br. J. Cancer 94 (4): 561â8. doi:10.1038/sj.bjc.6602972. PMC 2361183. PMID 16449996.
- Sharma G, Mirza S, Prasad CP, Srivastava A, Gupta SD, Ralhan R (April 2007). "Promoter hypermethylation of p16INK4A, p14ARF, CyclinD2 and Slit2 in serum and tumor DNA from breast cancer patients". Life Sci. 80 (20): 1873â81. doi:10.1016/j.lfs.2007.02.026. PMID 17383681.
- JabÅonowski Z, Reszka E, GromadziÅska J, WÄ sowicz W, Sosnowski M (June 2011). "Hypermethylation of p16 and DAPK promoter gene regions in patients with non-invasive urinary bladder cancer". Arch Med Sci 7 (3): 512â6. doi:10.5114/aoms.2011.23421. PMC 3258754. PMID 22295037.
- Xu R, Wang F, Wu L, Wang J, Lu C (January 2013). "A systematic review of hypermethylation of p16 gene in esophageal cancer". Cancer Biomark 13 (4): 215â26. doi:10.3233/CBM-130355. PMID 24240582.
- Oguejiofor KK, Hall JS, Mani N, Douglas C, Slevin NJ, Homer J, Hall G, West CM (November 2013). "The prognostic significance of the biomarker p16 in oropharyngeal squamous cell carcinoma". Clin Oncol (R Coll Radiol) 25 (11): 630â8. doi:10.1016/j.clon.2013.07.003. PMID 23916365.
- Balgkouranidou I, Liloglou T, Lianidou ES (February 2013). "Lung cancer epigenetics: emerging biomarkers". Biomark Med 7 (1): 49â58. doi:10.2217/bmm.12.111. PMID 23387484.
- Sinha P, Thorstad WT, Nussenbaum B, Haughey BH, Adkins DR, Kallogjeri D, Lewis Jr JS (November 2013). "Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: A critical analysis of patterns and outcomes". Oral Oncol. doi:10.1016/j.oraloncology.2013.10.007. PMID 24211084.
- Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE (August 2009). "Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging". Aging Cell 8 (4): 439â48. doi:10.1111/j.1474-9726.2009.00489.x. PMC 2752333. PMID 19485966.
- Dreyer JH, Hauck F, Oliveira-Silva M, Barros MH, Niedobitek G (April 2013). "Detection of HPV infection in head and neck squamous cell carcinoma: a practical proposal". Virchows Arch. 462 (4): 381â9. doi:10.1007/s00428-013-1393-5. PMID 23503925.
- Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE (2003). "Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways". Mol. Cancer Res. 1 (3): 195â206. PMID 12556559.
- Li J, Melvin WS, Tsai MD, Muscarella P (2004). "The nuclear protein p34SEI-1 regulates the kinase activity of cyclin-dependent kinase 4 in a concentration-dependent manner". Biochemistry 43 (14): 4394â9. doi:10.1021/bi035601s. PMID 15065884.
- Sugimoto M, Nakamura T, Ohtani N, Hampson L, Hampson IN, Shimamoto A, Furuichi Y, Okumura K, Niwa S, Taya Y, Hara E (1999). "Regulation of CDK4 activity by a novel CDK4-binding protein, p34(SEI-1)". Genes Dev. 13 (22): 3027â33. doi:10.1101/gad.13.22.3027. PMC 317153. PMID 10580009.
- Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Mol. Syst. Biol. 3: 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
- FÃ¥hraeus R, Paramio JM, Ball KL, LaÃn S, Lane DP (1996). "Inhibition of pRb phosphorylation and cell-cycle progression by a 20-residue peptide derived from p16CDKN2/INK4A". Curr. Biol. 6 (1): 84â91. doi:10.1016/S0960-9822(02)00425-6. PMID 8805225.
- Coleman KG, Wautlet BS, Morrissey D, Mulheron J, Sedman SA, Brinkley P, Price S, Webster KR (1997). "Identification of CDK4 sequences involved in cyclin D1 and p16 binding". J. Biol. Chem. 272 (30): 18869â74. doi:10.1074/jbc.272.30.18869. PMID 9228064.
- Russo AA, Tong L, Lee JO, Jeffrey PD, Pavletich NP (1998). "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a". Nature 395 (6699): 237â43. doi:10.1038/26155. PMID 9751050.
- Kaldis P, Ojala PM, Tong L, MÃ¤kelÃ¤ TP, Solomon MJ (2001). "CAK-independent activation of CDK6 by a viral cyclin". Mol. Biol. Cell 12 (12): 3987â99. doi:10.1091/mbc.12.12.3987. PMC 60770. PMID 11739795.
- Ivanchuk SM, Mondal S, Rutka JT (2008). "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle 7 (12): 1836â50. doi:10.4161/cc.7.12.6025. PMID 18583933.
- Rizos H, Diefenbach E, Badhwar P, Woodruff S, Becker TM, Rooney RJ, Kefford RF (2003). "Association of p14ARF with the p120E4F transcriptional repressor enhances cell cycle inhibition". J. Biol. Chem. 278 (7): 4981â9. doi:10.1074/jbc.M210978200. PMID 12446718.
- Zhang Y, Wolf GW, Bhat K, Jin A, Allio T, Burkhart WA, Xiong Y (2003). "Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway". Mol. Cell. Biol. 23 (23): 8902â12. doi:10.1128/MCB.23.23.8902-8912.2003. PMC 262682. PMID 14612427.
- Zhang Y, Xiong Y, Yarbrough WG (1998). "ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways". Cell 92 (6): 725â34. doi:10.1016/S0092-8674(00)81401-4. PMID 9529249.
- Clark PA, Llanos S, Peters G (2002). "Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2". Oncogene 21 (29): 4498â507. doi:10.1038/sj.onc.1205558. PMID 12085228.
- Pomerantz J, Schreiber-Agus N, LiÃ©geois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA (1998). "The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53". Cell 92 (6): 713â23. doi:10.1016/S0092-8674(00)81400-2. PMID 9529248.
- Vivo M, Calogero RA, Sansone F, CalabrÃ² V, Parisi T, Borrelli L, Saviozzi S, La Mantia G (2001). "The human tumor suppressor arf interacts with spinophilin/neurabin II, a type 1 protein-phosphatase-binding protein". J. Biol. Chem. 276 (17): 14161â9. doi:10.1074/jbc.M006845200. PMID 11278317.
- 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.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus Provide feedback
This family represents the N-terminus (approximately 50 residues) of cyclin-dependent kinase inhibitor 2a p19Arf, which seems to be restricted to mammals. This is a tumour-suppressor protein that has been shown to inhibit the growth of human tumour cells lacking functional p53 by inducing a transient G2 arrest and subsequently apoptosis .
Eymin B, Leduc C, Coll JL, Brambilla E, Gazzeri S; , Oncogene 2003;22:1822-1835.: p14ARF induces G2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. PUBMED:12660818 EPMC:12660818
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR010868
This entry represents the cyclin-dependent kinase inhibitor 2A, which seems to be restricted to mammals. This is a tumour-suppressor protein that has been shown to inhibit the growth of human tumour cells lacking functional p53 by inducing a transient G2 arrest and subsequently apoptosis [PUBMED:12660818].
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|Seed source:||Pfam-B_20449 (release 10.0)|
|Author:||Vella Briffa B|
|Number in seed:||6|
|Number in full:||33|
|Average length of the domain:||50.20 aa|
|Average identity of full alignment:||71 %|
|Average coverage of the sequence by the domain:||51.22 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||7|
|Download:||download the raw HMM for this family|
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As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the P19Arf_N domain has been found. There are 1 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
Loading structure mapping...