2Key Laboratory of Molecular Epigenetics, Ministry of Education, Northeast Normal University, 130024 Changchun, Jilin, P. R. China
3Central Laboratory of General Biology, School of Life Sciences, Northeast Normal University, 130024 Changchun, Jilin, P. R. China
* To whom correspondence should be addressed.
Received January 29, 2018; Revision received June 11, 2018
CDKN2A is one of the most studied tumor suppressor genes. It encodes the p16-INK4a protein that plays a critical role in the cell cycle progression, differentiation, senescence, and apoptosis. Mutations in CDKN2A or dysregulation of its functional activity are frequently associated with various types of human cancer. As a cyclin-dependent kinase inhibitor, p16-INK4a forms a complex with cyclin-dependent kinases 4/6 (CDK4/6) thereby competing with cyclin D. It is believed that the helix-turn-helix structures in the content of tandem ankyrin repeats in p16-INK4a are required for the protein interaction with CDK4. Until recently, the mechanisms considered to be involved in the regulation of p16-INK4a functions and cancer development have been mutations in DNA, homozygous or heterozygous gene loss, and methylation of CDKN2A promoter region. In this review, we discuss recent findings on the regulation of p16-INK4a by covalent modifications at both transcriptional and post-translational levels.
KEY WORDS: p16-INK4a, modification, methylation, phosphorylation, acetylation