The CIP/KIP proteins have broad specificity as compared to INK4
proteins for binding and inhibiting the cyclin-CDK complexes.
CHD has been reportedly linked with Antisense non-coding RNA in the INK4
locus (ANRIL) premotor DNA methylation.4 The differences in DNA methylation in vascular tissues with coronary artery disease may provide insight into the mechanisms underlying the development of atherosclerosis.
Antisense non-coding RNA in the INK4
locus (ANRIL) is a 3.8 kb IncRNA encoded in the chromosome 9p21 region and reported to be up-regulated in gastric cancer tissues (16, 17).
Pavletich, "Mechanisms of cyclin-dependent kinase regulation: Structures of Cdks, their cyclin activators, and Cip and INK4
inhibitors," Journal of Molecular Biology, vol.
Simultaneously, Klf4 cooperates with Oct4 and Sox2 in the suppression of the p21-encoding Ink4
locus, which then promotes the maintenance of proliferation .
Massague, "Kip/ Cip and Ink4
Cdk4 inhibitors cooperate to induce cell cycle arrest in response to TGF-beta," Genes and Development, vol.
Sherr, "Expression of the [p16.sup.INK4a] tumor suppressor versus other INK4
family members during mouse development and aging," Oncogene, vol.
These data are confirmed by studies in human which show that in patients with anthracycline-induced cardiomyopathy, there is a significant increase of senescent CPCs characterized by accumulation of p16 INK4
compared with age-matched controls [94, 97].
Cyclin-dependent kinases (CDKs) contains kinase domain with little kinase activity but on binding with Cyclin, the Cyclin/CDK become an active complex and cause the hyperphosphorylation of pRB that ultimately involve in regulation of transcription and mRNA processing while Cyclin/CDK complex is itself regulated by cell cycle inhibitors of the INK4
(inhibitors of CDK4) and CIP/KIP (CDK interacting protein/kinase inhibitory protein) families, especially p16Ink4a and p21Cip1 (Dyer and Bremner, 2005; Sage, 2012).
A clinician seeking to identify a trial containing a CDK4/6 inhibitor for a patient with an alteration in CDKN2A, which is also known as P16, INK4
, INK4A, ARF, and P16INK4A, would obtain variable results based on the gene name used in the search at ClinicalTrials.gov.
The negative regulation of Cdk/ cyclin complexes relies on two families of Cdk inhibitors; the INK4
family ([p16.sup.INK4a], [p15.sup.INK4b], [p18.sup.INK4c], [p19.sup.INK4d]) specifically bind to Cdk4 and Cdk6 and prevent D-type cyclin activity and the Cip/Kip family ([p21.sup.Cip1]/Waf1/Sdi1, [p27.sup.Kip1], [p57.sup.Kip2]) inhibits Cdk2/cyclin E, Cdk2/cyclin A, Cdk1/cyclin A, as well as Cdk1/cyclin B activity (for review see ).