Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase.
We screened cdc2 kinase inhibitors from cultured mediums of micro organisms using purified mouse cyclin B-cdc2 kinase and a specific substrate peptide for cdc2 kinase. A selective inhibitor of cdc2 kinase was isolated from the cultured medium of Aspergillus species F-25799, and identified 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, casein kinase I or epidermal growth factor-receptor tyrosine kinase. Its inhibitory effect was found to be due to competition with ATP. Butyrolactone I selectively inhibited the H1 histone phosphorylation in nuclear extracts. It also inhibited the phosphorylation of the product of retinoblastoma susceptibility gene in nuclear extracts and intact cells. Thus butyrolactone I should be very useful for elucidating the function of cdc2 and cdk2 kinases in cell cycle regulation.
Kitagawa
M
M
Banyu Tsukuba Research Institute, Merck Research Laboratories, Japan.
Okabe
T
T
Ogino
H
H
Matsumoto
H
H
Suzuki-Takahashi
I
I
Kokubo
T
T
Higashi
H
H
Saitoh
S
S
Taya
Y
Y
Yasuda
H
H
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000595:Amino Acid Sequence; D001230:Aspergillus / Q000737:chemistry; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D042846:CDC2-CDC28 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D006657:Histones / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D006656:Protamine Kinase / Q000037:antagonists & inhibitors; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016160:Retinoblastoma Protein / Q000378:metabolism; D013379:Substrate Specificity
D006657:Histones; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; C082868:butyrolactone I; D006656:Protamine Kinase; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D015107:4-Butyrolactone