CDC2-LIKE KINASES IN NORMAL AND MALIGNANT CELLS

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Recent studies have shown that there exists a family of mammalian protein kinases structurally and functionally related to the yeast cell cycle regulatory kinase cdc-2. Two members of the cdc2 family, p34/cdc2 and cdk2, have been identified in mammalian cells. p34/cdc2 kinase regulates the progression from G2 to M, and cdk2 has been proposed to regulate the progression from Gl to S phase (for review, see Pines and Hunter, Trends Cell Biol. 2: 72-76, 1992). We have cloned and structurally characterized a third member of the cdc2 kinase family with 58% amino acid sequence identity to mouse p34/cdc2 and 60% identity to human cdk2 (as a point of reference, p34/cdc2 and cdk2 have about 60% amino acid identity). The new kinase is called neuronal cdc2-like kinase (n-clk) because, in contrast to either p34/cdc2 or cdk2, n-clk is expressed at high levels in terminally differentiated neurons. Moreover, many cultured cell lines express high levels of n-clk mRNA as well as p34/cdc2 and cdk2 kinase. We plan to explore the role of n-clk in cell cycle regulation of mitotically active cells and human tumors, to determine if n-clk is a potential therapeutic target for specific kinase inhibitors. In addition, efforts will continue to develop convenient vectors for studying the interaction of drugs or small peptides with regulatory regions of n-clk. This study will proceed with analagous efforts studying kinases clearly important to cell cycle progression including p34/cdc2 kinase, MAP kinases and Gl p34 kinases which regulate p34/cdc2 activity.