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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)

Function: 1) induces cell cycle arrest in G1 & G2 phases 2) acts as a tumor suppressor 3) p16ink4A & related p15ink4B preferentially inhibit CDK4 & CDK6-cyclin complexes [1] 4) forms heterodimer with CDK4 or CDK6; this inhibits their ability to interact with cyclins D & to phosphorylate the retinoblastoma protein 5) isoform 3 does not bind to CDK4 6) does not interact with cyclins, CDC2, CDK2, or CDK5 7) binds to MDM2 & sequesters it in the nucleolus 8) blocks MDM2- induced degradation of p53 9) prevents activation of cyclin B1/CDC2 complexes 10) down-regulates BCL6-induced transcriptional repression 11) binds to E2F1 & MYC & blocks transcriptional activator activity 12) no effecton MYC transcriptional repression 13) binds to TOP1 & stimulates activity, complex (TOP1/ink4A) a) binds to rRNA gene promoters b) may play a role in rRNA transcription &/or maturation. 14) promotes its polyubiquitination & degradation of NPM1, thus inhibiting rRNA processing 15) enhances sumoylation of MDM2 & E2F 16) binds to HUWE1 & represses its ubiquitin ligase activity 17) expression increases in stem cells with age & diminishes cell proliferation [6] 18) binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1, TOP1 & UBE2I 19) p16ink4A appears to function independently of p53 & membrane signal transduction pathways 20) 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 Polymorphism: - genetic variations in CDKN2A may underlie susceptibility to uveal melanoma Pathology: 1) defects in CDKN2A are involved in tumor formation in a wide range of tissues 2) defects in CDKN2A are the cause of a) cutaneous malignant melanoma 2 b) familial atypical multiple mole melanoma-pancreatic carcinoma syndrome c) Li-Fraumeni syndrome d) melanoma-astrocytoma syndrome 3) 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] Comparative biology: - marker of senescent cells in mouse model for progeria [18] - cells expressing p16ink4A are dubbed 'senecent cells'

Interactions

molecular events

Related

melanoma multiple tumor suppressor-1 (MTS1); INK4; CDKN2A gene p16INK4a Ag in tissue

Specific

cyclin-dependent kinase inhibitor 2A, isoform 4; p14ARF; p19ARF (MLM)

General

anti-oncoprotein (tumor suppressor protein) cyclin-dependent kinase inhibitor (CDKI, CDKN) human longevity protein nuclear protein phosphoprotein

Properties

SIZE: entity length = 156 aa MW = 17 kD COMPARTMENT: cell nucleus MOTIF: ankyrin repeat NAME: ankyrin repeat SITE: 11-40 ankyrin repeat NAME: ankyrin repeat SITE: 44-72 ankyrin repeat NAME: ankyrin repeat SITE: 77-106 ankyrin repeat NAME: ankyrin repeat SITE: 110-139 INHIBITS: protein kinase

References

  1. Morgan DO. Principles of CDK regulation. Nature. 1995 Mar 9;374(6518):131-4. Review. PMID: 7877684
  2. 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: 8153634
  3. Marx [Research News] Science 264:344 1994
  4. 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: 7677168
  5. Entrez Gene :accession 1029
  6. 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
  7. CDKN2A Database Database of CDKN2A germline & somatic variants https://biodesktop.uvm.edu/perl/p16
  8. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN2aID146.html
  9. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDKN2A
  10. Wikipedia; P16INK4a entry http://en.wikipedia.org/wiki/P16INK4a
  11. UniProt :accession P42771
  12. CDKN2A Database Database of CDKN2A germline & somatic variants
  13. Atlas of genetics & cytogenetics in oncology & haematology http://atlasgeneticsoncology.org/genes/CDKN2aID146.html
  14. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=CDKN2A
  15. NIEHS-SNPs http://egp.gs.washington.edu/data/cdkn2a/
  16. 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: 22048312 - Peeper DS. Old cells under attack. Nature. 2011 Nov 2;479(7372):186 PMID: 22071762
  17. Sousa-Victor P et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 2014 Feb 20; 506:316. PMID: 24522534
  18. 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: 23212104
  19. 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: 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: 24136988 Free PMC Article

Component-of

molecular complex

Databases & Figures

OMIM correlations MORBIDMAP 600160 UniProt P42771 PFAM correlations Entrez Gene 1029 Kegg hsa:1029 Figures/diagrams/slides/tables related to p16ink4A