Fra -1, a Fos Gene Family Member That Activates Atrial Natriuretic Peptide Gene Transcription

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Abstract
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.