Kinases dépendantes des cyclines: rôle biologique et implications dans la pathologie humaine

Abstract

Les kinases dépendantes des cyclines (Cdk) occupent une place importante dans la régulation du cycle mitotique des cellules eucaryotes. La chronologie de leur activation est déterminée par leurs modifications post-traductionnelles (phosphorylations/déphosphorylations), et par l’association à une cycline, qui constitue la sous-unité régulatrice du complexe enzymatique. Les Cdk participent à la régulation du cycle cellulaire par la phosphorylation de la protéine Rb, des interactions avec des facteurs de transcription et la phosphorylation de l’histone H1 et d’autres composants de l’appareil mitotique. Une dérégulation des Cdk peut contribuer au développement d’un processus néoplasique, comme le suggèrent les interactions observées entre certaines Cdk et des oncoprotéines virales, et la délétion fréquente, dans des lignées néoplasiques et des tumeurs de novo, des gènes codant pour leurs inhibiteurs, p16INK4 et p15INK4B ou encore p21WAF1/CIP1. En revanche, c’est le déficit en la Cdk p58-GTA et non son hyperactivité, qui pourrait être impliqué dans la transformation néoplasique.

Cyclin dependent kinases (Cdks) is a family of serine-threonine protein kinases which plays a pivotal role in the eucaryote cell cycle regulation. The timing of their activation is dertermined by their post-translational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory subunit of the kinase complex. Cdks participate in the cell cycle regulation by phosphorylation of retinoblastoma susceptibility gene product (pRb) (Cdk4, Cdk6 and Cdk2), by interactions with transcription factors (Cdk2) and by phosphorylation of the histone H1 and other compounds of the mitotic apparatus (Cdk1). Cdk5 is probably not involved in the cell cycle regulation, but seems to participate in the cerebral metabolism. It was suggested that it plays a role in the pathogeny of Alzheimer's disease. p58-GTA is supposed to have an antiproliferative activity and to be involved in cellular death. The function of Cdk7 is to activate other Cdks. A deregulation of Cdks, especially consisting of their hyperexpression, may contribute to the development of neoplastic disorders. This hypothesis is corroborated by observations of interactions between some Cdks and viral oncoproteins: E1A of adenovirus, T antigen of simian virus 40, E6/E7 of human papilloma virus. Involvement of Cdks in neoplastic disorders may result either from hyperexpression of their genes, as the Cdk4 gene in brain tumors, or from inactivation of their inhibitors. The inhibitors concerned are p16(INK4) et p15(INK4B), whose genes are frequently deleted in cancer cell lines and fresh tumors, and p21(WAF1/GIP1), whose expression is p53-dependent and therefore may be impaired as a result of the inactivation of this oncoprotein. As for p58-GTA, contrarily to the cell cycle activating Cdks, it may be involved in the neoplastic transformation as a results of its deficiency.