CYCLIN-DEPENDENT KINASES - BIOLOGICAL FUN CTIONS AND INVOLVEMENT IN HUMAN PATHOLOGY

Cyclin dependent kinases (Cdks) is a family of serine-threonine protei n kinases which plays a pivotal role in the eucaryote cell cycle regul ation. The timing of their activation is determined by their post-tran slational modifications (phosphorylations/dephosphorylations), and by the association of a protein called cyclin, which is the regulatory su bunit of the kinase complex. Cdks participate in the cell cycle regula tion by phosphorylation of retinoblastoma susceptibility gene product (pRb) (Cdk4, Cdk6 and Cdk2), by interactions with transcription factor s (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 metabo lism. It was suggested that it plays a role in the pathogeny of Alzhei mer's disease. p58-GTA is supposed to have an antiproliferative activi ty and to be involved in cellular death. The function of Cdk7 is to ac tivate other Cdks. A deregulation of Cdks, especially consisting of th eir, hyperexpression, may contribute to the development of neoplastic disorders. This hypothesis is corroborated by observations of interact ions between some Cdks and viral oncoproteins: E1A of adenovirus, T an tigen 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 inactivati on of their inhibitors. The inhibitors concerned are p16(INK4) et p15( INK4B), whose genes are frequently deleted in cancer cell lines and fr esh tumors, and p21(WAF1/CIP1), whose expression is p53-dependent and therefore may be impaired as a result of the inactivation of this onco protein. As for p58-GTA, contrarily to the cell cycle activating Cdks, it may be involved in the neoplastic transformation as a results of i ts deficiency.