Fra-1, a Fos gene family member that activates atrial natriuretic peptide gene transcription.
Previous studies suggested that individual components of the activator protein 1 (AP-1) complex behave in a highly idiosyncratic fashion at the level of the human atrial natriuretic peptide (ANP) gene promoter. ANP gene transcription is activated by c-jun and is generally suppressed by c-fos. In the present study, fra-1, a close relative of the c-fos gene product in terms of its structure and functional activity, behaved like fos in cardiac atriocytes, effecting an approximately 50% reduction in c-jun-activatable expression of a human ANP chloramphenicol acetyltransferase (CAT) reporter. In cardiac ventriculocytes, however, fra-1 effected a synergistic amplification of the c-jun response (a 2.5-fold increase over c-jun alone). In atrial cells, fos-like proteins were not uniformly inhibitory in that a carboxy terminal deletion mutant of c-fos activated a human ANP-CAT reporter in the atriocyte cultures. Finally, using a series of domain-swap mutations in the fos/fra structural sequences, we showed that sequences at both the amino and the carboxy termini are required to realize the full fra-1-dependent stimulatory effect as well as the c-fos-dependent inhibition of ANP gene transcription. These findings suggest considerable heterogeneity in the response of the ANP promoter to different components of the AP-1 complex. Such heterogeneity may serve to broaden the range of biological responses available to this promoter as the cardiac cell attempts to adapt to perturbations in the extracellular environment.
Kovacic-Milivojevic
B
B
Metabolic Research Unit, University of California at San Francisco 94143, USA.
Gardner
D G
DG
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D016762:Genes, fos; D016758:Genes, jun; D006321:Heart / Q000502:physiology; D006325:Heart Atria; D006352:Heart Ventricles; D005810:Multigene Family; D009206:Myocardium / Q000166:cytology; D051381:Rats; D014158:Transcription, Genetic
D009320:Atrial Natriuretic Factor