Concept
INK4 is a family of cyclin-dependent kinase inhibitors (CKIs). The members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4 (hence their name INhibitors of CDK4), and of CDK6. The other family of CKIs, CIP/KIP proteins are capable of inhibiting all CDKs. Enforced expression of INK4 proteins can lead to G1 arrest by promoting redistribution of Cip/Kip proteins and blocking cyclin E-CDK2 activity. In cycling cells, there is a resassortment of Cip/Kip proteins between CDK4/5 and CDK2 as cells progress through G1. Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair. INK4 proteins are tumor suppressors and loss-of-function mutations lead to carcinogenesis. INK4 proteins are highly similar in terms of structure and function, with up to 85% amino acid similarity. They contain multiple ankyrin repeats. The INK4a/ARF/INK4b locus encodes three genes (p15INK4b, ARF, and p16INK4a) in a 35-kilobase stretch of the human genome. P15INK4b has a different reading frame that is physically separated from p16INK4a and ARF. P16INK4a and ARF have different first exons that are spliced to the same second and third exon. While those second and third exons are shared by p16INK4a and ARF, the proteins are encoded in different reading frames meaning that p16INK4a and ARF are not isoforms, nor do they share any amino acid homology. Polymorphisms of the p15INK4b/p16INK4a homolog were found to segregate with melanoma susceptibility in the Xiphophorus indicating that INK4 proteins have been involved with tumor suppression for over 350 million years. Furthermore, the older INK4-based system has been further bolstered by the evolution of the recent addition of the ARF-based anti-cancer response. INK4 proteins are cell-cycle inhibitors. When they bind to CDK4 and CDK6, they induce an allosteric change that leads to the formation of CDK-INK4 complexes rather than CDK-cyclin complexes.