STRUCTURE OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P19(INK4D)

Citation
Fy. Yuh et al., STRUCTURE OF THE CYCLIN-DEPENDENT KINASE INHIBITOR P19(INK4D), Nature, 389(6654), 1997, pp. 999-1003
Citations number
30
Categorie Soggetti
Multidisciplinary Sciences
Journal title
NatureACNP
ISSN journal
00280836
Volume
389
Issue
6654
Year of publication
1997
Pages
999 - 1003
Database
ISI
SICI code
0028-0836(1997)389:6654<999:SOTCKI>2.0.ZU;2-T
Abstract
In cancer, the biochemical pathways that are dominated by the two tumo ur-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity a nd they are, in turn, specifically inhibited by the Ink4 family of cyc lin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 p hase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subu nit Cdk4, and the CDKI p16(Ink4a), which alter the protein or its leve l of expression, are all strongly implicated in cancer. This suggests that the Rb 'pathway' is of particular importance(1). Here we report t he structure of the p19(Ink4d) protein, determined by NMR spectroscopy (2-4). The structure indicates that most mutations to the p16(Ink4a) g ene, which result in loss of function, are due to incorrectly folded a nd/or insoluble protein(5). We propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6 complexes that might provide a basis for the design of therapeutics against cancer.