p16

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

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]

Nomenclature

p16 is also known as:

Gene

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

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 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

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

High grade squamous intraepithelial lesion showing strong p16 staining.

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. 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]

It has been used as a target to delay some aging changes in mice.[34]

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][35]

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:

See also

References

  1. 1 2 "Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)".
  2. ↑ 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. PMID 8152487. doi:10.1038/368753a0.
  3. ↑ 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.
  4. 1 2 3 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. PMID 8259215. doi:10.1038/366704a0.
  5. ↑ Hamosh, Ada. "Cyclin-dependent kinase inhibitor 2A; CDKN2A". OMIM. Retrieved 10 December 2013.
  6. ↑ "Molecular biology of cancer", Oxford University Press, 2005, ISBN 978-0-19-926472-8, Section 5.3
  7. ↑ Roussel MF (September 1999). "The INK4 family of cell cycle inhibitors in cancer". Oncogene. 18 (38): 5311–7. PMID 10498883. doi:10.1038/sj.onc.1202998.
  8. ↑ 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. PMID 16957737. doi:10.1038/nature05092.
  9. 1 2 3 4 Rayess H, Wang MB, Srivatsan ES (April 2012). "Cellular senescence and tumor suppressor gene p16". Int. J. Cancer. 130 (8): 1715–25. PMC 3288293 Freely accessible. PMID 22025288. doi:10.1002/ijc.27316.
  10. 1 2 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 Freely accessible. PMID 8622687.
  11. ↑ 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. PMID 12351676. doi:10.1126/science.1076997.
  12. ↑ 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. PMC 1820894 Freely accessible. PMID 17344414. doi:10.1101/gad.415507.
  13. 1 2 Liggett WH, Sidransky D (March 1998). "Role of the p16 tumor suppressor gene in cancer". J. Clin. Oncol. 16 (3): 1197–206. PMID 9508208.
  14. ↑ Rocco JW, Sidransky D (March 2001). "p16(MTS-1/CDKN2/INK4a) in cancer progression". Exp. Cell Res. 264 (1): 42–55. PMID 11237522. doi:10.1006/excr.2000.5149.
  15. ↑ 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. PMID 7726912. doi:10.1038/ng0994-27.
  16. ↑ 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. PMID 8589035. doi:10.1002/gcc.2870140306.
  17. ↑ 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.
  18. ↑ 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. PMC 4112445 Freely accessible. PMID 24935963. doi:10.1136/jmedgenet-2014-102320.
  19. ↑ 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. PMID 8093026. doi:10.1006/bbrc.1994.2294.
  20. ↑ 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. PMC 4039222 Freely accessible. PMID 24742402. doi:10.18632/oncotarget.1444.
  21. ↑ 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. PMC 3805925 Freely accessible. PMID 24155659. doi:10.7150/ijms.6884.
  22. ↑ 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. PMID 22106032. doi:10.1002/hed.21949.
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  27. 1 2 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. PMID 23916365. doi:10.1016/j.clon.2013.07.003.
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  34. ↑ Baker DJ; et al. (2011). "Clearance of p16Ink4a-Positive Senescent Cells Delays Aging-Associated Disorders". Nature. 479: 232–236. PMC 3468323 Freely accessible. PMID 22048312. doi:10.1038/nature10600.
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  45. 1 2 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. PMID 12446718. doi:10.1074/jbc.M210978200.
  46. 1 2 3 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. PMC 262682 Freely accessible. PMID 14612427. doi:10.1128/MCB.23.23.8902-8912.2003.
  47. 1 2 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. PMID 9529249. doi:10.1016/S0092-8674(00)81401-4.
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