The INK4 family of cell cycle inhibitors in cancer.

Abstract

Since the discovery of p16 (Serrano et al., 1993) and p21 (El-Deiry et al., 1993; Harper et al., 1993; Xiong et al., 1993), the cyclin-dependent kinase inhibitors (CKIs) have been intensively investigated. CKIs include two distinct families, the INK4 (INhibitors of CDK4) family, whose four members (p16, p15, p18, p19) exclusively bind to and inhibit the D-type cyclin-dependent kinases (CDK4 and CDK6), and the CIP/KIP family, whose three members (p21, p27, p57) are able to inhibit the activity of all CDKs (Sherr and Roberts, 1995). The roles of these cell cycle inhibitors are being elucidated through studies of mouse knock-out models, gene expression in cell lines, and genetic screens of human tumors. Enforced expression of any of the CKIs results in growth arrest in the G1 phase and prevents entry into the DNA synthetic (S) phase (Sherr and Roberts, 1995). Growth arrest is accomplished by inhibiting retinoblastoma protein (pRB) phosphorylation (Ewen, 1994), and thus the release of the E2F transcription factors, which are required for the transcriptional activation of genes necessary for DNA synthesis (Dyson, 1998; Nevins, 1998). These similar biological and biochemical properties suggested that CKIs might act as tumor suppressors and that deletion, mutation, or transcriptional repression of the CKI genes would lead to uncontrolled cell growth and cancer. Screens of human tumors for genetic alterations (including mutations, deletions, rearrangements, or promoter hypermethylation and silencing), and the creation and analyses of knock-out mice, clearly implicate the INK4a/ARF locus, as an important target in cancer. In contrast, the other INK4 or CIP/ KIP loci do not appear to be involved in the etiology of cancer (Hirama and Koe‚er, 1995; Hall and Peters, 1996; Drexler, 1998). Several excellent reviews on CKIs (Harper and Elledge, 1996; Nakayama and Nakayama, 1998) and the roles of p16 (Ruas and Peters, 1998) and the INK4a/ARF locus in cancer have been recently published (Sherr, 1998; Sharpless and DePinho, 1999). Therefore, here, I will review only the most recent data (from our institution and from others), on the alterations of the INK4 genes in human tumors, and the functional signi®cance of targeted deletions of INK4 genes in the mouse, alone or in combination with the deletions of other CKIs. The INK4 family: chromosomal location and structure