Details

Autor(en) / Beteiligte

• Roussel, M F

Titel

The INK4 family of cell cycle inhibitors in cancer

Ist Teil von

• Oncogene, 1999-09, Vol.18 (38), p.5311-5317

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

1999

Quelle

MEDLINE

Beschreibungen/Notizen

• Since the discovery of p16 super(INK4a) and p21 super(CIP1), 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 super(INK4a), p15 super(INK4b), p18 super(INK4c), p19 super(INK4d)) exclusively bind to and inhibit the D-type cyclin-dependent kinases (CDK4 and CDK6), and the CIP/KIP family, whose three members (p21 super(CIP1/WAF1), p27 super(KIP1), p57 super(KIP2)) are able to inhibit the activity of all CDKs. 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. Growth arrest is accomplished by inhibiting retinoblastoma protein (pRB) phosphorylation, and thus the release of the E2F transcription factors, which are required for the transcriptional activation of genes necessary for DNA synthesis. 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. Several excellent reviews on CKIs and the roles of p16 super(INK4a) and the INK4a/ARF locus in cancer have been recently published. 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.