CDKN2A

(redirected from INK4A)

CDKN2A

A gene on chromosome 9p21 that encodes an alternate open reading frame (ARF) product, which acts as a tumour suppressor by binding to MDM2 and blocking its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits MDM2’s oncogenic activity, which would normally degrade p53, a tumour suppressor protein. CDKN2A also induces G2 arrest and apoptosis, independent of p53, by preventing the activation of cyclin B1/CDC2 complexes.

CDKN2A also binds to:
• BCL6, downregulating BCL6-induced transcriptional repression;
• E2F1 and MYC, blocking their transcriptional activator activity;
• HUWE1, repressing its ubiquitin ligase activity;
• TOP1/TOPOI, stimulating its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation.

CDKN2A interacts with:
• COMMD1 and promotes its “Lys63”-linked polyubiquitination;
• NPM1/B23, promoting its polyubiquitination and degradation and inhibiting rRNA processing;
• UBE2I/UBC9, enhacing sumoylation of some of its binding partners (e.g., MDM2 and E2F1).
References in periodicals archive ?
Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16(INK4A) overexpression and clinicopathological correlations.
Molecular analysis of the INK4A and INK4B gene loci in human breast cancer cell lines and primary carcinomas.
Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a).
Among these, miR141 was confirmed to regulate the tumor suppressor gene INK4A in two cell lines with increased miR-141 expression (LUTFUL et al., 2015).
(25.) Govindarajan B, Klafter R, Miller MS, Mansur C, Mizesko M, Bai X, LaMontagne K Jr, Arbiser JL: Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase.
Promoter hypermethylation: A common cause of reduced p16(INK4a) expression in uveal melanoma.
Inactivation of the free E2F can result from repression by INK4A family repressors (p15, p16, p18, and p19) and CIP/KIP family repressors (p21, p27, and p57) that prevent the G1/S transition [77-79].
Chang et al., "Human papillomavirus DNA and P16 INK4A expression in concurrent esophageal and gastric cardia cancers," World Journal of Gastroenterology, vol.
Gleiberman et al., "Aging of mice is associated with p16(Ink4a)- and beta-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells," Aging, vol.
CDKN2A methylation may lead to the development of malignant disease by increased p16(INK4A)/p14(ARF) expression [26-28].
Aboussekhra, "p16 (INK4A) induces senescence and inhibits EMT through microRNA141/microRNA-146b-5p-dependent repression of AUF1," Molecular Carcinogenesis, vol.
Munoz-Cabello et al., "Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a," Molecular Cell, vol.