Herbimycin A induces G1 arrest through accumulation of p27(Kip1) in cyclin D1-overexpressing fibroblasts

Biochem Biophys Res Commun. 2000 Jan 7;267(1):54-8. doi: 10.1006/bbrc.1999.1927.

Abstract

The ansamycin antibiotic herbimycin A is a potent tyrosine kinase inhibitor and reduces the growth rate of various types of mammalian cells. When quiescent Rat6 fibroblast cells were treated with herbimycin A, serum-induced expression of cyclin D1 was inhibited, and this was associated with inhibition of G1 phase progression. However, herbimycin A also inhibited serum-induced G1 progression in derivatives of the Rat6 fibroblast cell line that stably overexpress a human cyclin D1 cDNA (R6ccnD1#4 cells), without affecting the expression levels of G1 cyclins. We found that herbimycin A prevented serum-induced downregulation of the cyclin-dependent kinase inhibitor p27(Kip1), thereby leading to inactivation of the protein kinase activity of CDK2. These results suggest that herbimycin A inhibits a tyrosine kinase(s) that plays a role in degradation of the p27(Kop1) protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones
  • CDC2-CDC28 Kinases*
  • Cell Cycle / drug effects*
  • Cell Cycle Proteins*
  • Cell Line
  • Culture Media, Serum-Free
  • Cyclin D1 / genetics*
  • Cyclin D1 / physiology*
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors
  • Cyclin-Dependent Kinases / metabolism
  • Enzyme Inhibitors / metabolism*
  • Fibroblasts
  • G1 Phase / drug effects
  • Gene Expression Regulation / drug effects
  • Humans
  • Lactams, Macrocyclic
  • Microtubule-Associated Proteins / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Quinones / pharmacology*
  • Rats
  • Recombinant Proteins / metabolism
  • Rifabutin / analogs & derivatives
  • S Phase / drug effects
  • Transfection
  • Tumor Suppressor Proteins*

Substances

  • Benzoquinones
  • Cdkn1b protein, rat
  • Cell Cycle Proteins
  • Culture Media, Serum-Free
  • Enzyme Inhibitors
  • Lactams, Macrocyclic
  • Microtubule-Associated Proteins
  • Quinones
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Rifabutin
  • herbimycin
  • Protein Serine-Threonine Kinases
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cdk2 protein, rat
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases