P16 (gene)

Cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4), also known as CDKN2A, is a human gene.

This gene generates several transcript variants which 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 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This 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 ["Molecular biology of cancer", Oxford University Press, 2005, ISBN 978-0-19-926472-8, Section 5.3] . In spite of the 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 cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [cite web | title = Entrez Gene: CDKN2A cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1029| accessdate = ]

p16 is a tumour suppressor gene. Mutations in p16 increase the risk of developing a variety of cancers, notably melanoma. p16 is an important gene in regulating the cell cycle.

Recent research on the p16 gene, published in Nature in September 2006, indicates that its increased expression 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.

The p16 gene has an alternative reading frame (ARF) that encodes the p14 ARF protein. this is involved in stabilising P53 and is positively regulated by E2F.

"p16INK4a" is a major product of the CDKN2A locus. Its alternate reading frame product is p14ARF. p16INK4a regulates the cell cycle by binding and deactivating various cyclin-CDKcomplexes. A study published in 2007 in the New England Journal of medicine established that there is a strong association between polymorphisms on chromosome 9p21.3 (SNP, rs1333049) and coronary artery disease. This region codes for the INK4 proteins p16INK4a and p15INK4b. The corresponding genes are CDKN2A and CDKN2B. The proteins may inhibit cell growth induced by Transforming Growth Factor-beta.

References

Further reading

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citations =
*cite journal | author=Smith-Sørensen B, Hovig E |title=CDKN2A (p16INK4A) somatic and germline mutations. |journal=Hum. Mutat. |volume=7 |issue= 4 |pages= 294–303 |year= 1996 |pmid= 8723678 |doi= 10.1002/(SICI)1098-1004(1996)7:4<294::AID-HUMU2>3.0.CO;2-9
*cite journal | author=Dracopoli NC, Fountain JW |title=CDKN2 mutations in melanoma. |journal=Cancer Surv. |volume=26 |issue= |pages= 115–32 |year= 1996 |pmid= 8783570 |doi=
*cite journal | author=Akita H |title= [Prognostic importance of altered expression of cell cycle regulators in lung cancer] |journal=Nippon Rinsho |volume=60 Suppl 5 |issue= |pages= 267–71 |year= 2003 |pmid= 12101670 |doi=
*cite journal | author=Kusy S, Larsen CJ, Roche J |title=p14ARF, p15INK4b and p16INK4a methylation status in chronic myelogenous leukemia. |journal=Leuk. Lymphoma |volume=45 |issue= 10 |pages= 1989–94 |year= 2005 |pmid= 15370242 |doi= 10.1080/10428190410001714025
*cite journal | author=Gjerset RA |title=DNA damage, p14ARF, nucleophosmin (NPM/B23), and cancer. |journal=J. Mol. Histol. |volume=37 |issue= 5-7 |pages= 239–51 |year= 2007 |pmid= 16855788 |doi= 10.1007/s10735-006-9040-y
*cite journal | author=Yildiz IZ, Usubütün A, Firat P, "et al." |title=Efficiency of immunohistochemical p16 expression and HPV typing in cervical squamous intraepithelial lesion grading and review of the p16 literature. |journal=Pathol. Res. Pract. |volume=203 |issue= 6 |pages= 445–9 |year= 2007 |pmid= 17543474 |doi= 10.1016/j.prp.2007.03.010

External links

* [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=full_report&list_uids=1029 p16 description at Entrez Gene]
* [http://www.upi.com/NewsTrack/view.php?StoryID=20060906-023232-7367r "Scientists study mammalian aging"] at United Press International
* – ^{[http://scholar.google.co.uk/scholar?hl=en&lr=&q=author%3A+intitle%3Ap16INK4a+induces+an+age-dependent+decline+in+islet+regenerative+potential&as_publication=Nature&as_ylo=2006&as_yhi=2006&btnG=Search Scholar search]}
* NEJM 2007 [http://content.nejm.org/cgi/content/abstract/357/5/443 Genomewide Association Analysis of Coronary Artery Disease]

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