Butyrolactone I, a selective inhibitor of cdk2 and cdc2 kinase

Oncogene. 1993 Sep;8(9):2425-32.

Abstract

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.

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / pharmacology
  • Amino Acid Sequence
  • Aspergillus / chemistry
  • CDC2 Protein Kinase / antagonists & inhibitors*
  • CDC2-CDC28 Kinases*
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases*
  • Histones / metabolism
  • In Vitro Techniques
  • Kinetics
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Protamine Kinase / antagonists & inhibitors
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors*
  • Protein Serine-Threonine Kinases*
  • Retinoblastoma Protein / metabolism
  • Substrate Specificity

Substances

  • Histones
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Retinoblastoma Protein
  • butyrolactone I
  • Protamine Kinase
  • Protein Serine-Threonine Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinases
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • 4-Butyrolactone