E. Espinos et Mj. Weber, ACTIVATION OF THE MAP KINASE CASCADE BY HISTONE DEACETYLASE INHIBITORS IS REQUIRED FOR THE STIMULATION OF CHOLINE-ACETYLTRANSFERASE GENE PROMOTER, Molecular brain research, 56(1-2), 1998, pp. 118-124
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.