BUTYROLACTONE-I, A SELECTIVE INHIBITOR OF CDK2 AND CDC2 KINASE

We screened cdc2 kinase inhibitors from cultured mediums of micro orga nisms using purified mouse cyclin B-cdc2 kinase and a specific substra te peptide for cdc2 kinase. A selective inhibitor of cdc2 kinase was i solated from the cultured medium of Aspergillus species F-25799, and i dentified as butyrolactone I. Butyrolactone I inhibited cdc2 and cdk2 kinases but it had little effect on mitogen-activated protein kinase, protein kinase C, cyclic-AMP dependent kinase, casein kinase II, casei n kinase I or epidermal growth factor-receptor tyrosine kinase. Its in hibitory effect was found to be due to competition with ATP. Butyrolac tone I selectively inhibited the H1 histone phosphorylation in nuclear extracts. It also inhibited the phosphorylation of the product of ret inoblastoma susceptibility gene in nuclear extracts and intact cells. Thus butyrolactone I should be very useful for elucidating the functio n of cdc2 and cdk2 kinases in cell cycle regulation.