ACTIVATION OF THE MAP KINASE CASCADE BY HISTONE DEACETYLASE INHIBITORS IS REQUIRED FOR THE STIMULATION OF CHOLINE-ACETYLTRANSFERASE GENE PROMOTER

We previously described that the major promoter (M) of human choline a cetyltransferase (ChAT) gene is activated by three inhibitors of histo ne deacetylase, butyrate, trichostatin and trapoxin, in transfected CH P126 neuroepithelioma cells. We now show that trapoxin and butyrate tr iggered a rapid and transient phosphorylation of ERK1/2 kinases, that was suppressed by PD98059, a highly specific inhibitor of MAP kinase k inase MEK1. The stimulation of ChAT promoter activity by trapoxin or b utyrate did not require ongoing protein synthesis, and was suppressed by PD98059. The ovenexpression of dominant negative mutants of H-ras o r ERK2 proteins depressed ChAT promoter activation by trapoxin in tran sient transfection assays. Conversely, the overexpression of constitut ively active mutants of H-ras or MEK1 proteins had little or no effect on ChAT promoter activity, but strongly synergized with trapoxin. The se 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. (C) 1998 Elsevier Scie nce B.V.