[Transformation with the E1A + cHa-ras oncogenes enhances the trans-repressor function of the Elk-1 transcription factor].
Rat embryo fibroblasts (REF) transformed with the complementing E1A and cHa-ras oncogenes show a down-regulation of the c-fos early response gene, which is transcribed with the participation of Elk-1. The role of Elk-1 was studied with constructs coding for the full-length factor or its N- or C-terminal fragment fused with Gal. The trans-activating effect of each construct on the Gal4-Luc reporter plasmid was estimated in contransfected REF52 and E1A + cHa-ras cells stimulated with serum or treated with sodium butyrate, a histone deacetylase inhibitor. In E1A + cHa-ras cells, serum activated the expression of C-terminal Gal-Elk(206-428) but not that of full-length Gal-Elk(1-428). The serum-induced activation of Gal-Elk(206-428) was suppressed by PD98059, a MEK/ERK inhibitor, and enhanced by SB203580, an inhibitor of the p38-kinase cascade. It was assumed that p38 negatively affects the MEK/ERK cascade, which plays the major role in the Elk-1 activation in response to serum. Sodium butyrate enhanced the Gal-Elk(1-428) activity both in serum-stimulated and in starving E1A - cHa-ras cells, suggesting a high activity of Elk-1-phosphorylating kinases in the latter. The butyrate-mediated activation of Gal-Elk(206-428) and Gal-Elk(1-428) was suppressed by PD98059 and, therefore, depended on the MEK/ERK cascade. Thus, Elk-1 acted not only as a positive, but also as a negative transcription regulator. Possibly, to suppress transcription, Elk-1 binds with histone deacetylases and thereby contributes to the inactive chromatin state in E1A + cHa-ras cells.
Usenko
T N
TN
Institute of Cytology, Russian Academy of Sciences, St. Petersburg, 194064 Russia.
Pospelova
T V
TV
Pospelov
V A
VA
D017500:Adenovirus E1A Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology; D005419:Flavonoids / Q000494:pharmacology; D011905:Genes, ras; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050807:ets-Domain Protein Elk-1
D017500:Adenovirus E1A Proteins; D002087:Butyrates; D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020928:Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one