p16ink4A; cyclin-dependent kinase inhibitor 2A, isoforms 1/2/3; cyclin-dependent kinase 4 inhibitor A; CDK4I; p16-INK4a; p16INK4A; p16-INK4; multiple tumor suppressor 1; MTS-1; p16MTS1 (CDKN2A, CDKN2, MTS1)
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Function
- induces cell cycle arrest in G1 & G2 phases
- acts as a tumor suppressor
- p16ink4A & related p15ink4B preferentially inhibit CDK4 & CDK6-cyclin complexes[1]
- forms heterodimer with CDK4 or CDK6; this inhibits their ability to interact with cyclins D & to phosphorylate the retinoblastoma protein
- isoform 3 does not bind to CDK4
- does not interact with cyclins, CDC2, CDK2, or CDK5
- binds to MDM2 & sequesters it in the nucleolus
- blocks MDM2- induced degradation of p53
- prevents activation of cyclin B1/CDC2 complexes
- down-regulates BCL6-induced transcriptional repression
- binds to E2F1 & MYC & blocks transcriptional activator activity
- no effecton MYC transcriptional repression
- binds to TOP1 & stimulates activity, complex (TOP1/ink4A)
- promotes its polyubiquitination & degradation of NPM1, thus inhibiting rRNA processing
- enhances sumoylation of MDM2 & E2F
- binds to HUWE1 & represses its ubiquitin ligase activity
- expression increases in stem cells with age & diminishes cell proliferation[6]
- binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1, TOP1 & UBE2I
- p16ink4A appears to function independently of p53 & membrane signal transduction pathways
- p16ink4A accumulates in cell lines deficient in Rb suggesting that p16ink4A & Rb share some functional relationship[4]
Structure
- belongs to the CDKN2 cyclin-dependent kinase inhibitor family
- contains 4 ANK repeats
Alternative splicing
named isoforms=4
Expression
- widely expressed
- not detected in brain or skeletal muscle
- isoform 3 is pancreas-specific
Pathology
- defects in CDKN2A are involved in tumor formation in a wide range of tissues
- defects in CDKN2A are the cause of
- accumulation of p16ink4a in senescent cells may disrupt tissue structure & function & contribute to age-related pathology[16]; clearance of p16ink4a-containing cells may prevent &/or attenuate age-related degenerative pathology[16]
Polymorphism
- genetic variations in CDKN2A may underlie susceptibility to uveal melanoma
Comparative biology
- marker of senescent cells in mouse model for progeria[18]
- cells expressing p16ink4A are dubbed 'senecent cells'
More general terms
- phosphoprotein
- nuclear protein
- anti-oncoprotein (tumor suppressor protein)
- cyclin-dependent kinase inhibitor (CDKI, CDKN)
- human longevity protein
More specific terms
Additional terms
References
- ↑ 1.0 1.1 Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7877684
- ↑ Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS 3rd, Johnson BE, Skolnick MH. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994 Apr 15;264(5157):436-40. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8153634
- ↑ Marx [Research News] Science 264:344 1994
- ↑ 4.0 4.1 Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995 Sep;147(3):545-60. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7677168
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1029
- ↑ 6.0 6.1 Jansen V et al, Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a Nature 2006 (Sept 6) http://dx.doi.org/10.1038/nature05159
Molofsky AV et al, Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during aging. Nature 2006 http://dx.doi.org/10.1038/nature05091
Krishnamurthy J et al, p16INK4a induces age-dependent decline in islet regenerative potential Nature 2006 http://dx.doi.org/10.1038/nature05092 - ↑ CDKN2A Database Database of CDKN2A germline & somatic variants https://biodesktop.uvm.edu/perl/p16
- ↑ Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN2aID146.html
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDKN2A
- ↑ Wikipedia; P16INK4a entry http://en.wikipedia.org/wiki/P16INK4a
- ↑ UniProt http://www.uniprot.org/uniprot/P42771.html
- ↑ CDKN2A Database Database of CDKN2A germline & somatic variants
- ↑ Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN2aID146.html
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDKN2A
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/cdkn2a/
- ↑ 16.0 16.1 16.2 Baker DJ, Wijshake T, Tchkonia T Clearance of p16Ink4a-positive senescent cells delays ageing- associated disorders. Nature. 2011 Nov 2;479(7372):232-6 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22048312
Peeper DS. Old cells under attack. Nature. 2011 Nov 2;479(7372):186 PMID: https://www.ncbi.nlm.nih.gov/pubmed/22071762 - ↑ Sousa-Victor P et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 2014 Feb 20; 506:316. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24522534
- ↑ 18.0 18.1 Naylor RM, Baker DJ, van Deursen JM. Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther. 2013 Jan;93(1):105-16 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23212104
- ↑ Burd CE, Sorrentino JA, Clark KS et al Monitoring tumorigenesis and senescence in vivo with a p16(INK4a)-luciferase model. Cell. 2013 Jan 17;152(1-2):340-51. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23332765 Free PMC Article
LaPak KM, Burd CE. The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res. 2014 Feb;12(2):167-83. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24136988 Free PMC Article
Database
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:1029
- OMIM: https://mirror.omim.org/entry/151623
- OMIM: https://mirror.omim.org/entry/155601
- OMIM: https://mirror.omim.org/entry/155720
- OMIM: https://mirror.omim.org/entry/155755
- OMIM: https://mirror.omim.org/entry/600160
- OMIM: https://mirror.omim.org/entry/606719
- UniProt: http://www.uniprot.org/uniprot/P42771.html
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=1029