TRANSCRIPTIONAL ACTIVATION OF THE FRA-1 GENE BY AP-1 IS MEDIATED BY REGULATORY SEQUENCES IN THE FIRST INTRON

Constitutive expression of c-Fos, FosB, Fra-1, or c-Jun in rat fibrobl asts leads to up-regulation of the immediate-early gene fra-1. Using t he posttranslational FosER induction system, we demonstrate that this AP-1 dependent stimulation of fra-1 expression is rapid, depends on a functional DNA-binding domain of FosER, and is a general phenomenon ob served in different cell types. In vitro mutagenesis and functional an alysis of the rat fra-1 gene in stably transfected Rat-1A-FosER fibrob lasts indicated that basal and AP-1-regulated expression of the fra-1 gene depends on regulatory sequences in the first intron which compris e a consensus AP-1 site and two AP-1-like elements. We have also inves tigated the transactivating and transforming properties of the Fra-1 p rotein to address the significance of fra-1 up-regulation. The entire Fra-1 protein fused to the DNA-binding domain of Ga14 is shown to lark any transactivation function, and yet it possesses oncogenic potentia l, as overexpression of Fra-1 in established rat fibroblasts results i n anchorage-independent growth in vitro and tumor development in athym ic mice. fra-1 is therefore not only induced by members of the Fos fam ily, but its gene product may also contribute to cellular transformati on by these proteins. Together, these data identify fra-1 as a unique member of the fos gene family which is under positive control by AP-1 activity.