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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/14 22:30:56」(JST)

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この項目では、タンパク質について説明しています。戦闘機については「P-16 (航空機)」をご覧ください。

サイクリン依存性キナーゼ阻害2A (melanoma, p16, inhibits CDK4) は、CDKN2Aとも言い、ヒトのCDKN2A（p16）遺伝子によりコード化されているがん抑制タンパク質である^[1]^[2]^[3]。p16は細胞周期の調整に重要な役割を果たしており、p16の変異は様々な癌、特にメラノーマの発生のリスクを高めている。なお、CDK（cyclin-dependent kinase）とはサイクリン依存性キナーゼの略である。

機能

p16遺伝子は、最初のエクソンが異なるいくつかの転写変異体を生成する。明確なタンパク質をコード化している少なくとも3つの可変な結合変異体が報告されており、そのうち2つはCDK4キナーゼ阻害機能として知られている構造的に関連した異性体をコード化している。遺伝子の残りの20000塩基対分の上流に位置する最初のエクソンを含んだ残りの転写変異体は、腫瘍抑制タンパク質p14ARF（ARF）を含んでいる。このARFは癌抑制タンパク質であるp53の働きを弱める作用を有するMDM2に干渉し隔離するため、ARFはP53を安定化する役割を持っている^[4]。

構造的及び機能的な相違に関わらず、細胞周期G1期のCDK4及びp53の調整機能を通じてp16遺伝子によりコード化されたCKD阻害異性体及びAFR生成物が細胞周期のG1期で通常の機能の役割を行っている。p16遺伝子は、様々な癌においてしばしば変異しているか欠落しており、重要ながん抑制遺伝子として知られている^[1]。

組織が老化したときのp16遺伝子の発現の増加は幹細胞の増殖を減退させる^[5]。細胞老化と関連して癌のリスクは増加しているが、幹細胞の分裂と増殖のこれらの減退は、癌からの脅威から守っている。

臨床的意義

CDKN2A（p16）遺伝子の変異は、幅広い癌の発生のリスクに関連しており、遺伝子の変異は癌の培養細胞で多く認められている^[6]^[7]。例えば次のような例がある。

膵臓腺癌は、CDKN2A（p16）遺伝子の変異としばしば関係している^[8]^[9]^[10]。
p16の欠落は、食道癌と胃癌の培養細胞からしばしば見つかっている^[11]。
p16INK4aの濃度は、組織の老化に伴って飛躍的に上昇する。それゆえp16INK4aは、分子レベルでどの程度早く組織が老化しているかを測定する血液検査に応用できる可能性がある^[11]。
p16蛋白に対する免疫染色はHPV検査に対する病理組織上での代理マーカーである。HPVに感染して宿主細胞の細胞増殖機構に異常をきたした不死化細胞はp16過剰発現を示す。^[12]

脚注

^ ^a ^b “Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)”. 2011年1月31日閲覧。
^ Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (April 1994). “Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers”. Nature 368 (6473): 753–6. doi:10.1038/368753a0. PMID 8152487.
^ Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A (July 1995). “Complex structure and regulation of the P16 (MTS1) locus”. Cancer Res. 55 (14): 2988–94. PMID 7606716.
^ "Molecular biology of cancer", Oxford University Press, 2005, ISBN 978-0-19-926472-8, Section 5.3
^ Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (September 2006). “p16INK4a induces an age-dependent decline in islet regenerative potential”. Nature 443 (7110): 453–7. doi:10.1038/nature05092. PMID 16957737.
^ Liggett WH, Sidransky D (March 1998). “Role of the p16 tumor suppressor gene in cancer”. J. Clin. Oncol. 16 (3): 1197–206. PMID 9508208.
^ Rocco JW, Sidransky D (March 2001). “p16(MTS-1/CDKN2/INK4a) in cancer progression”. Exp. Cell Res. 264 (1): 42–55. doi:10.1006/excr.2000.5149. PMID 11237522.
^ Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH et al. (September 1994). “Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma”. Nat. Genet. 8 (1): 27–32. doi:10.1038/ng0994-27. PMID 7726912.
^ 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): 189–95. 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): 405–12. PMID 7624155.
^ ^a ^b Igaki H, Sasaki H, Kishi T, Sakamoto H, Tachimori Y, Kato H, Watanabe H, Sugimura T et al. (September 1994). “Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines”. Biochem. Biophys. Res. Commun. 203 (2): 1090–5. doi:10.1006/bbrc.1994.2294. PMID 8093026.
^ 佐野孝昭、吉田朋美、福田利夫　HPV 病理と臨床　2011　Vol.29 臨時増刊号　p294

wiki en

[Wiki en表示]

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.^[1]^[2]^[3] 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, cervical cancer, and esophageal cancer. p16 can be used to improve the histological diagnostic accuracy of CIN3. 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 “open reading frame of 148 amino acids encoding a protein of molecular weight 15,845 comprising four ankyrin repeats.”^[4] p16Ink4A is named after its molecular weight and its role in inhibiting CDK4.^[4]

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

p16 is also known as:

p16^Ink4A
p16^Ink4
Cyclin-dependent kinase inhibitor 2A (CDKN2A)
CDKN2
CDK 4 Inhibitor
Multiple Tumor Suppressor 1 (MTS1)
TP16
ARF
MLM
P14
P19

Gene

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.^[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

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

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

Role in cancer

Mutations in 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]

Clinical use

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.^[27]^[28]^[29]

p16 FISH

p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.^[30]

p16 immunochemistry

gynecologic cancers

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

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

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.^[32]

It has been used as a target to delay some aging changes in mice.^[33]

Experimental analysis of p16 mutation

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]^[34]

Discovery

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

P16 (gene) has been shown to interact with:

CCNG1,^[35]
CDK4,^[4]^[36]^[37]^[38]^[39]^[40]
CDK6,^[39]^[41]^[42]
DAXX,^[43]
E4F1,^[44]
MDM2,^[43]^[45]^[46]^[47]^[48]
P53,^[44]^[45]^[46]
PPP1R9B,^[49]
RPL11,^[45] and
SERTAD1.^[36]^[37]

References

^ ^a ^b "Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)".
^ Nobori T, Miura K, Wu DJ, Lois A, Takabayashi K, Carson DA (April 1994). "Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers". Nature 368 (6473): 753–6. doi:10.1038/368753a0. PMID 8152487.
^ Stone S, Jiang P, Dayananth P, Tavtigian SV, Katcher H, Parry D, Peters G, Kamb A (July 1995). "Complex structure and regulation of the P16 (MTS1) locus". Cancer Res. 55 (14): 2988–94. PMID 7606716.
^ ^a ^b ^c Serrano M, Hannon GJ, Beach D (December 1993). "A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4". Nature 366 (6456): 704–7. doi:10.1038/366704a0. PMID 8259215.
^ Hamosh, Ada. "Cyclin-dependent kinase inhibitor 2A; CDKN2A". OMIM. Retrieved 10 December 2013.
^ "Molecular biology of cancer", Oxford University Press, 2005, ISBN 978-0-19-926472-8, Section 5.3
^ Roussel MF (September 1999). "The INK4 family of cell cycle inhibitors in cancer". Oncogene 18 (38): 5311–7. doi:10.1038/sj.onc.1202998. PMID 10498883.
^ Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (September 2006). "p16INK4a induces an age-dependent decline in islet regenerative potential". Nature 443 (7110): 453–7. doi:10.1038/nature05092. PMID 16957737.
^ ^a ^b ^c ^d Rayess H, Wang MB, Srivatsan ES (April 2012). "Cellular senescence and tumor suppressor gene p16". Int. J. Cancer 130 (8): 1715–25. doi:10.1002/ijc.27316. PMC 3288293. PMID 22025288.
^ ^a ^b 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): 859–67. 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): 1039–43. doi:10.1126/science.1076997. PMID 12351676.
^ Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch 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): 525–30. doi:10.1101/gad.415507. PMC 1820894. PMID 17344414.
^ ^a ^b Liggett WH, Sidransky D (March 1998). "Role of the p16 tumor suppressor gene in cancer". J. Clin. Oncol. 16 (3): 1197–206. PMID 9508208.
^ Rocco JW, Sidransky D (March 2001). "p16(MTS-1/CDKN2/INK4a) in cancer progression". Exp. Cell Res. 264 (1): 42–55. doi:10.1006/excr.2000.5149. PMID 11237522.
^ Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (September 1994). "Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma". Nat. Genet. 8 (1): 27–32. doi:10.1038/ng0994-27. PMID 7726912.
^ 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): 189–95. 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): 405–12. PMID 7624155.
^ Helgadottir H, Höiom V, Jönsson G, Tuominen R, Ingvar C, Borg A, Olsson H, Hansson J. (August 2014). "High risk of tobacco-related cancers in CDKN2A mutation-positive melanoma families". J Med Genet. 51 (8): 545–52. doi:10.1136/jmedgenet-2014-102320. PMID 24935963.
^ 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): 1090–5. doi:10.1006/bbrc.1994.2294. PMID 8093026.
^ Puig-Butille JA, Escámez MJ, Garcia-Garcia F, Tell-Marti G, Fabra À, Martínez-Santamaría L, Badenas C, Aguilera P, Pevida M, Dopazo J, del Río M, Puig S. (March 2014). "Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer.". Oncotarget 5 (6): 1439–51. PMID 24742402.
^ 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): 1727–39. doi:10.7150/ijms.6884. PMC 3805925. PMID 24155659.
^ Demokan S, Chuang A, Suoğlu Y, Ulusan M, Yalnız 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): 1470–5. 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): 561–8. 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): 1873–81. doi:10.1016/j.lfs.2007.02.026. PMID 17383681.
^ Jabłonowski Z, Reszka E, Gromadzińska J, Wąsowicz 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): 512–6. 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): 215–26. doi:10.3233/CBM-130355. PMID 24240582.
^ ^a ^b 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): 630–8. 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): 49–58. 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. 50 (1): 45–51. doi:10.1016/j.oraloncology.2013.10.007. PMID 24211084.
^ Hwang H, Tse C, Rodriguez S, Gown A, Churg A (2014). "p16 FISH Deletion in Surface Epithelial Mesothelial Proliferations Is Predictive of Underlying Invasive Mesothelioma". Am. J. Surg. Pathol. 38 (5): 681–8. doi:10.1097/PAS.0000000000000176. PMID 24503757.
^ ^a ^b Cioffi-Lavina M, Chapman-Fredricks J, Gomez-Fernandez C, Ganjei-Azar P, Manoharan M, Jorda M (2010). "P16 expression in squamous cell carcinomas of cervix and bladder". Appl. Immunohistochem. Mol. Morphol. 18 (4): 344–7. doi:10.1097/PAI.0b013e3181d2bbd7. PMID 20571342.
^ 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): 439–48. doi:10.1111/j.1474-9726.2009.00489.x. PMC 2752333. PMID 19485966.
^ Darren; et al. (2011). "Clearance of p16Ink4a-Positive Senescent Cells Delays Aging-Associated Disorders". Nature 479: 232–236. doi:10.1038/nature10600.
^ 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): 381–9. 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): 195–206. PMID 12556559.
^ ^a ^b 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): 4394–9. doi:10.1021/bi035601s. PMID 15065884.
^ ^a ^b 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): 3027–33. 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.
^ ^a ^b Fåhraeus R, Paramio JM, Ball KL, Laín 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): 84–91. 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): 18869–74. 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): 237–43. doi:10.1038/26155. PMID 9751050.
^ Kaldis P, Ojala PM, Tong L, Mäkelä TP, Solomon MJ (2001). "CAK-independent activation of CDK6 by a viral cyclin". Mol. Biol. Cell 12 (12): 3987–99. doi:10.1091/mbc.12.12.3987. PMC 60770. PMID 11739795.
^ ^a ^b Ivanchuk SM, Mondal S, Rutka JT (2008). "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle 7 (12): 1836–50. doi:10.4161/cc.7.12.6025. PMID 18583933.
^ ^a ^b 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): 4981–9. doi:10.1074/jbc.M210978200. PMID 12446718.
^ ^a ^b ^c 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): 8902–12. doi:10.1128/MCB.23.23.8902-8912.2003. PMC 262682. PMID 14612427.
^ ^a ^b 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): 725–34. 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): 4498–507. doi:10.1038/sj.onc.1205558. PMID 12085228.
^ Pomerantz J, Schreiber-Agus N, Liégeois 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): 713–23. doi:10.1016/S0092-8674(00)81400-2. PMID 9529248.
^ Vivo M, Calogero RA, Sansone F, Calabrò 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): 14161–9. doi:10.1074/jbc.M006845200. PMID 11278317.

External links

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.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 頭頚部癌に関連するヒトパピローマウイルス human papillomavirus associated head and neck cancer
2. 膵外分泌癌の分子学的病因 molecular pathogenesis of exocrine pancreatic cancer
3. 前立腺癌の分子生物学 molecular biology of prostate cancer
4. 頭頸部の扁平上皮癌化：分子学的および遺伝学的変化 head and neck squamous cell carcinogenesis molecular and genetic alterations
5. ヒトパピローマウイルス（HPV）感染のウイルス学および癌との関連 virology of human papillomavirus infections and the link to cancer

English Journal

Sensitive colorimetric biosensing for methylation analysis of p16/CDKN2 promoter with hyperbranched rolling circle amplification.

Geng Y1, Wu J2, Shao L3, Yan F4, Ju H5.
Biosensors & bioelectronics.Biosens Bioelectron.2014 Nov 15;61:593-7. doi: 10.1016/j.bios.2014.06.010. Epub 2014 Jun 10.
A simple, fast and sensitive colorimetric biosensing method for DNA methylation analysis was developed by combining methylation-sensitive endonuclease based digestion with hyperbranched rolling circle amplification (HRCA) induced signal enhancement. The assay was carried out on a DNA capture probe m
PMID 24956567

Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

Lim AM1, Do H, Young RJ, Wong SQ, Angel C, Collins M, Takano EA, Corry J, Wiesenfeld D, Kleid S, Sigston E, Lyons B, Fox SB, Rischin D, Dobrovic A, Solomon B.
International journal of cancer. Journal international du cancer.Int J Cancer.2014 Aug 15;135(4):887-95. doi: 10.1002/ijc.28727. Epub 2014 Jan 30.
CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. F
PMID 24436120

Novel recombinant GII.P16_GII.13 and GII.P16_GII.3 norovirus strains in Italy.

Medici MC1, Tummolo F2, Martella V3, Giammanco GM4, De Grazia S4, Arcangeletti MC2, De Conto F2, Chezzi C2, Calderaro A2.
Virus research.Virus Res.2014 Aug 8;188:142-5. doi: 10.1016/j.virusres.2014.04.005. Epub 2014 Apr 19.
Novel norovirus strains are continuously emerging worldwide. Molecular investigation and phylogenetic analysis identified GII.P16 recombinant noroviruses from the stools of four Italian children with gastroenteritis. The capsid gene was characterized as either GII.13 or GII.3. The GII.P16_GII.13 Ita
PMID 24751799

Japanese Journal

P16 口臭治療に関する歯科衛生士の意識調査(ポスター6,第39回福岡歯科大学学会総会抄録)

加塩奈津希,米田雅裕,内田初美,鈴木奈央,内藤徹,縄田和歌子,黒田美和子,力武紗由美,廣藤卓雄
福岡歯科大学学会雑誌 38(増補), 41, 2012-11-12
NAID 110009554243

Overexpression of cell cycle regulator CDCA3 promotes oral cancer progression by enhancing cell proliferation with prevention of G1 phase arrest

Uchida Fumihiko,Uzawa Katsuhiro,Kasamatsu Atsushi,Takatori Hiroaki,Sakamoto Yosuke,Ogawara Katsunori,Shiiba Masashi,Tanzawa Hideki,Bukawa Hiroki,内田文彦,武川寛樹
BMC cancer 12(321), 2012-07-00
… Further, there was up-regulation of the cyclin-dependent kinase inhibitors (p21Cip1, p27Kip1, p15INK4B, and p16INK4A) in the knockdown cells.ConclusionThe current results showed that overexpression of CDCA3 occurs frequently during oral carcinogenesis and this overexpression might be associated closely with progression of OSCCs by preventing the arrest of cell-cycle progression at the G1 phase via decreased expression of the cyclin-dependent kinase inhibitors. …
NAID 120004898305

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★リンクテーブル★

リンク元	「膠芽腫」「癌抑制遺伝子」
拡張検索	「p16INK4A遺伝子」「p16遺伝子」「p16 gene」「cyclin-dependent kinase inhibitor p16」「サイクリン依存性キナーゼ阻害因子p16」
関連記事	「p」

「膠芽腫」

Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus
	solution structure of the n-terminal 37 amino acids of the mouse arf tumor suppressor protein
Identifiers
Symbol	P19Arf_N
Pfam	PF07392
InterPro	IPR010868
SCOP	1hn3
SUPERFAMILY	1hn3
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Cyclin-dependent kinase inhibitor 2A
	PDB rendering of p16INK4A based on 1a5e.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1A5E, 1BI7, 1DC2, 2A5E
Identifiers
Symbols	CDKN2A ; ARF; CDK4I; CDKN2; CMM2; INK4; INK4A; MLM; MTS-1; MTS1; P14; P14ARF; P16; P16-INK4A; P16INK4; P16INK4A; P19; P19ARF; TP16
External IDs	OMIM: 600160 MGI: 104738 HomoloGene: 55430 GeneCards: CDKN2A Gene
Gene ontology
Molecular function	• p53 binding; • DNA binding; • cyclin-dependent protein serine/threonine kinase inhibitor activity; • protein binding; • transcription factor binding; • protein kinase binding; • poly(A) RNA binding; • NF-kappaB binding; • ubiquitin-protein transferase inhibitor activity; • MDM2/MDM4 family protein binding;
Cellular component	• nucleus; • nucleoplasm; • nucleolus; • cytoplasm; • mitochondrion; • cytosol; • nuclear body; • senescence-associated heterochromatin focus; • protein complex;
Biological process	• G1/S transition of mitotic cell cycle; • protein polyubiquitination; • mitotic cell cycle; • mitophagy; • negative regulation of cell-matrix adhesion; • transcription, DNA-templated; • rRNA processing; • negative regulation of protein kinase activity; • activation of cysteine-type endopeptidase activity involved in apoptotic process; • cell cycle arrest; • Ras protein signal transduction; • negative regulation of cell proliferation; • apoptotic mitochondrial changes; • regulation of G2/M transition of mitotic cell cycle; • protein sumoylation; • negative regulation of cell growth; • negative regulation of B cell proliferation; • regulation of protein stability; • protein destabilization; • negative regulation of NF-kappaB transcription factor activity; • negative regulation of immature T cell proliferation in thymus; • positive regulation of protein sumoylation; • positive regulation of smooth muscle cell apoptotic process; • senescence-associated heterochromatin focus assembly; • negative regulation of phosphorylation; • positive regulation of apoptotic process; • positive regulation of DNA damage response, signal transduction by p53 class mediator; • post-translational protein modification; • cellular protein metabolic process; • negative regulation of cyclin-dependent protein serine/threonine kinase activity; • negative regulation of transcription, DNA-templated; • positive regulation of transcription, DNA-templated; • positive regulation of transcription from RNA polymerase II promoter; • regulation of protein export from nucleus; • somatic stem cell division; • protein stabilization; • negative regulation of ubiquitin-protein transferase activity; • mitochondrial depolarization; • protein K63-linked ubiquitination; • positive regulation of cell cycle arrest; • cellular senescence; • replicative senescence; • positive regulation of protein localization to nucleus; • positive regulation of signal transduction by p53 class mediator; • regulation of apoptotic DNA fragmentation; • negative regulation of proteolysis involved in cellular protein catabolic process; • regulation of protein targeting to mitochondrion; • negative regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process; • positive regulation of macrophage apoptotic process; • positive regulation of cellular senescence;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

サイクリン依存性キナーゼ阻害2A (melanoma, p16, inhibits CDK4)
	PDB rendering based on 1a5e.
PDBに登録されている構造
PDB	Ortholog search: PDBe, RCSB, PDBj
PDBのIDコード一覧
	1a5e, 1bi7, 1dc2, 2a5e
識別記号
記号（英語版）	CDKN2A; ARF; CDK4I; CDKN2; CMM2; INK4; INK4a; MLM; MTS1; TP16; p14; p14ARF; p16; p16INK4; p16INK4a; p19
その他ID	OMIM（英語版）: 600160 HomoloGene（英語版）: 55430 GeneCards: CDKN2A Gene
遺伝子オントロジー
分子機能	• DNA binding; • cyclin-dependent protein kinase inhibitor activity; • protein binding; • kinase activity;
細胞の構成要素	• cellular_component; • nucleus; • nucleoplasm; • nucleolus; • cytoplasm;
生物学的プロセス	• cell cycle checkpoint; • regulation of cyclin-dependent protein kinase activity; • transcription; • regulation of transcription, DNA-dependent; • rRNA processing; • apoptosis; • cell cycle; • cell cycle arrest; • cell aging; • negative regulation of cell proliferation; • epidermis development; • negative regulation of cyclin-dependent protein kinase activity;
	出典: Amigo / EGO
RNA発現パターン
	その他参照発現データ
オルソログ

　　[★]

英: glioblastoma
同: 神経膠芽腫、多形膠芽腫 glioblastoma multiforme; グリア芽細胞腫、グリア芽腫、膠芽細胞腫、グリオブラストーマ、膠芽腫、神経膠芽細胞腫
関: 脳腫瘍、星状細胞腫

神経系 091009IV

分類

原発性脳腫瘍

神経膠腫 glioma

星状細胞腫 astrocytoma

膠芽腫 glioblastoma

概念

肉眼的・組織的に多彩な形態を示すので多形膠芽腫とも呼ばれる(SCN.170)

病因

primary dlioblastoma：genetic defects(EGFR amplification, MDM2 overexpression, p16 deletion, PTEN mutation)：older patients
secondary glioblastoma：p53 tumor suppressor gene inactivating → PDGF-A amplification：young patiens

病理

壊死、出血、嚢胞形成 (SCN.170)
大小様々の円型、紡錘型、不整型の細胞が密に増殖 (SCN.170)
腫瘍内の様々な壊死。壊死周囲に核が柵状に配列する所見(nuclear pseudopalisading, pseudopalisading necrosis)、血管の増殖、内皮細胞の増殖(SCN.170)