Activation of the MAP kinase cascade by histone deacetylase inhibitors is required for the stimulation of choline acetyltransferase gene promoter.

Abstract

We previously described that the major promoter (M) of human choline acetyltransferase (ChAT) gene is activated by three inhibitors of histone deacetylase, butyrate, trichostatin and trapoxin, in transfected CHP126 neuroepithelioma cells. We now show that trapoxin and butyrate triggered a rapid and transient phosphorylation of ERK1/2 kinases, that was suppressed by PD98059, a highly specific inhibitor of MAP kinase kinase MEK1. The stimulation of ChAT promoter activity by trapoxin or butyrate did not require ongoing protein synthesis, and was suppressed by PD98059. The overexpression of dominant negative mutants of H-ras or ERK2 proteins depressed ChAT promoter activation by trapoxin in transient transfection assays. Conversely, the overexpression of constitutively active mutants of H-ras or MEK1 proteins had little or no effect on ChAT promoter activity, but strongly synergized with trapoxin. These data thus suggest that the activation of the MEK/ERK kinase cascade plays a necessary, but not sufficient, role in the regulation of ChAT promoter by inhibitors of histone deacetylase.

• Authors: E Espinos, M J Weber
• Journal: Brain research. Molecular brain research (Brain Res Mol Brain Res) Vol. 56 Issue 1-2 Pg. 118-24 (May 1998) ISSN: 0169-328X [Print] Netherlands
• PMID: 9602089 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 1998 Elsevier Science B.V.

Chemical References

• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Choline O-Acetyltransferase
• Calcium-Calmodulin-Dependent Protein Kinases

Topics

• Calcium-Calmodulin-Dependent Protein Kinases (metabolism)
• Choline O-Acetyltransferase (genetics, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Histone Deacetylase Inhibitors
• Humans
• Promoter Regions, Genetic (drug effects)
• Tumor Cells, Cultured