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The INK4 family of cell cycle inhibitors in cancer

Oncogene volume 18, pages 5311–5317 (1999)Cite this article

Since the discovery of p16INK4a (Serrano et al., 1993) and p21CIP1 (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 (p16INK4a, p15INK4b, p18INK4c, p19INK4d) exclusively bind to and inhibit the D-type cyclin-dependent kinases (CDK4 and CDK6), and the CIP/KIP family, whose three members (p21CIP1/WAF1, p27KIP1, p57KIP2) 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 Koeffler, 1995; Hall and Peters, 1996; Drexler, 1998). Several excellent reviews on CKIs (Harper and Elledge, 1996; Nakayama and Nakayama, 1998) and the roles of p16INK4a (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 significance of targeted deletions of INK4 genes in the mouse, alone or in combination with the deletions of other CKIs.

Enforced expression of INK4 proteins arrests cells in the G1 phase, in a pRB-dependent fashion (Lukas et al., 1995; Medema et al., 1995). In this scenario, CDK4 is redistributed from cyclin D-CDK4 complexes to INK4-CDK4 complexes, and unbound D-type cyclin is rapidly degraded by the ubiquitin-dependent proteasome degradation pathway (Diehl et al., 1997). Loss of D-type cyclins prevents the titration of p27KIP1 by cyclin D-CDK4 and -CDK6 complexes away from cyclin E-CDK2 and cyclin A-CDK2 complexes. As a result, there is complete inhibition of cyclin E-CDK2 and cyclin A-CDK2 activities, pRB phosphorylation, and exit from the G1 phase. There is no evidence that CDK4 and CDK6 molecules in complexes with INK4 proteins are recycled, therefore, INK4 proteins can be viewed as being analogous to ‘trash cans’ for CDK4 and CDK6 (Sherr and Roberts, 1999). These recent revelations into the shared role of INK4 proteins in sequestering CDK4 and CDK6 might explain why the deletion of a single INK4 member does not always lead to phenotypic effects (see below).

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Acknowledgements

I am deeply indebted to John Cleveland, Veronika Sexl and Frederique Zindy for their criticisms and comments of this review and Julia-Cay Jones for scientific editing, Charles Sherr for his continuous support and the members of the Roussel/Sherr laboratories for helpful discussions. MF Roussel is funded by NIH grant PO1 CA-71907, the Cancer Core CA-21765, and the American Lebanese Syrian Associated Charities (ALSAC) of St Jude Children's Research Hospital.

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  1. Department of Tumor Cell Biology, St Jude Children's Research Hospital, 322 North Lauderdale, Memphis, TN 38105, Tennessee, USA

    Martine F Roussel

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Roussel, M. The INK4 family of cell cycle inhibitors in cancer. Oncogene 18, 5311–5317 (1999). https://doi.org/10.1038/sj.onc.1202998

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