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(Hypertension. 1995;25:679-682.)
© 1995 American Heart Association, Inc.

Articles

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

Branka Kovacic-Milivojevic; David G. Gardner

From the Metabolic Research Unit and Department of Medicine, University of California at San Francisco.

Correspondence to David G. Gardner, MD, Metabolic Research Unit, Box 0540 1141 HSW, University of California at San Francisco, San Francisco, CA 94143.

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.

Key Words: atrial natriuretic peptide • genes, fos • heart hypertrophy • gene expression

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