Ras inhibits Jun-activated human atrial natriuretic peptide gene transcription in cultured ventricular myocytes.
p21ras is a potent regulator of myogenic cell growth and differentiation. It has been implicated as playing a major role in the genesis of cardiac hypertrophy. We examined the effect of Ras overexpression on human atrial natriuretic peptide (hANP) gene expression, a marker of hypertrophy, in neonatal rat ventricular myocytes. Transient transfection of Haras, which expresses an activated form of p21ras, effected a modest stimulation of basal hANP-chloramphenicol acetyl transferase (hANPCAT) expression. Noteworthy, the same construct inhibited both c-Jun- and Jun B-stimulated hANPCAT activity (60% and 80%, respectively). Cotransfection of a dominant-negative Ras mutant reversed this inhibition completely. The inhibitory effect was promoter selective in this system. Of those tested, only the hANP and cardiac troponin T promoters were suppressed by Ras. The inhibitory effect appears to operate through a Ras-mediated increase in c-Fos activity as evidenced by (1) the absence of additivity of the Ha-Ras- and c-Fos-mediated inhibition at higher levels of proto-oncogene expression, (2) Ras-dependent activation of c-fos gene transcription, inferred from the induction of a c-fos chloramphenicol acetyl transferase reporter (3.4-fold), and (3) reversal of Ras inhibition by a c-fos antisense oligonucleotide but not by a scrambled DNA sequence of identical base composition or the complementary sense oligonucleotide. Our findings suggest that p21tas can exert a wide range of effects on the phenotype of the cardiac ventricular myocyte. The direction that these effects take appears largely to be a function of the preexisting activation state of the cell.
Kovacic-Milivojevic
B
B
Department of Medicine, University of California at San Francisco 94143, USA.
Zlock
D W
DW
Gardner
D G
DG
D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D002478:Cells, Cultured; D016232:Endothelins / Q000494:pharmacology; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000502:physiology*; D011905:Genes, ras / Q000502:physiology*; D006352:Heart Ventricles / Q000187:drug effects; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051381:Rats; D016276:Ventricular Function
D016232:Endothelins; C000715470:MAS1 protein, human; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D009320:Atrial Natriuretic Factor; D015689:Oncogene Protein p21(ras)