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 fibroblasts leads to up-regulation of the immediate-early gene fra-1. Using the 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 observed in different cell types. In vitro mutagenesis and functional analysis of the rat fra-1 gene in stably transfected Rat-1A-FosER fibroblasts indicated that basal and AP-1-regulated expression of the fra-1 gene depends on regulatory sequences in the first intron which comprise a consensus AP-1 site and two AP-1-like elements. We have also investigated the transactivating and transforming properties of the Fra-1 protein 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 lack any transactivation function, and yet it possesses oncogenic potential, as overexpression of Fra-1 in established rat fibroblasts results in anchorage-independent growth in vitro and tumor development in athymic mice, fra-1 is therefore not only induced by members of the Fos family, but its gene product may also contribute to cellular transformation 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.
Bergers
G
G
Research Institute of Molecular Pathology, Vienna, Austria.
Graninger
P
P
Braselmann
S
S
Wrighton
C
C
Busslinger
M
M
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004967:Estrogens / Q000494:pharmacology; D005786:Gene Expression Regulation; D016762:Genes, fos / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008969:Molecular Sequence Data; D015513:Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics*; D051381:Rats; D011960:Receptors, Estrogen / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D015534:Trans-Activators; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic; D000099169:Fos-Related Antigen 1
D004967:Estrogens; D015513:Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D011960:Receptors, Estrogen; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1