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Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron.

ABSTRACT: 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.

SUBMITTER: Bergers G

PROVIDER: S-EPMC230613 | biostudies-other | 1995 Jul

REPOSITORIES: biostudies-other

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Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron.

Bergers G G Graninger P P Braselmann S S Wrighton C C Busslinger M M

Molecular and cellular biology 19950701 7

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 indi ...[more]

PMID: 7791782

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Project description:BackgroundIntron mediated enhancement (IME) is the potential of introns to enhance the expression of its respective gene. This essential function of introns has been observed in a wide range of species, including fungi, plants, and animals. However, the mechanisms underlying the enhancement are as of yet poorly understood. The goal of this study was to identify potential IME-related sequence motifs and genomic features in first introns of genes in Arabidopsis thaliana.ResultsBased on the rationale that functional sequence motifs are evolutionarily conserved, we exploited the deep sequencing information available for Arabidopsis thaliana, covering more than one thousand Arabidopsis accessions, and identified 81 candidate hexamer motifs with increased conservation across all accessions that also exhibit positional occurrence preferences. Of those, 71 were found associated with increased correlation of gene expression of genes harboring them, suggesting a cis-regulatory role. Filtering further for effect on gene expression correlation yielded a set of 16 hexamer motifs, corresponding to five consensus motifs. While all five motifs represent new motif definitions, two are similar to the two previously reported IME-motifs, whereas three are altogether novel. Both consensus and hexamer motifs were found associated with higher expression of alleles harboring them as compared to alleles containing mutated motif variants as found in naturally occurring Arabidopsis accessions. To identify additional IME-related genomic features, Random Forest models were trained for the classification of gene expression level based on an array of sequence-related features. The results indicate that introns contain information with regard to gene expression level and suggest sequence-compositional features as most informative, while position-related features, thought to be of central importance before, were found with lower than expected relevance.ConclusionsExploiting deep sequencing and broad gene expression information and on a genome-wide scale, this study confirmed the regulatory role on first-introns, characterized their intra-species conservation, and identified a set of novel sequence motifs located in first introns of genes in the genome of the plant Arabidopsis thaliana that may play a role in inducing high and correlated gene expression of the genes harboring them.

Project description:ABSTRACT: Exposure to abiotic stresses triggers global changes in the expression of thousands of eukaryotic genes at the transcriptional 70 and post-transcriptional levels. Small RNA (smRNA) pathways and splicing both function as crucial mechanisms regulating stress-responsive gene expression. However, examples of smRNAs regulating gene expression remain largely limited to effects on mRNA stability, translation, and epigenetic regulation. Also, our understanding of the networks controlling plant gene expression in response to environmental changes, and examples of these regulatory pathways intersecting, remains limited. Here, to investigate the role of smRNAs in stress responses we examined smRNA transcriptomes of Brachypodium distachyon plants subjected to various abiotic stresses. We found that exposure to different abiotic stresses specifically induced a group 75 of novel, endogenous small interfering RNAs (stress-induced, UTR-derived siRNAs, or sutr-siRNAs) that originate from the 3M-bM-^@M-2 UTRs of a subset of coding genes. Our bioinformatics analyses predicted that sutr-siRNAs have potential regulatory functions and that over 90% of sutr-siRNAs target intronic regions of many mRNAs in trans. Importantly, a subgroup of these sutr- siRNAs target the important intron regulatory regions, such as branch point sequences, that could affect splicing. Our study indicates that in Brachypodium, sutr-siRNAs may affect splicing by masking or changing accessibility of specific cis-elements 80 through base-pairing interactions to mediate gene expression in response to stresses. We hypothesize that this mode of regulation of gene expression may also serve as a general mechanism for regulation of gene expression in plants and potentially in other eukaryotes. Analysis of smRNA populations in Brachypodium plants challenged by abiotic stresses: To profile the populations of smRNAs in the model monocot Brachypodium distachyon and examine their regulation in response to abiotic stresses, we conducted high-throughput sequencing of small RNAs from plants exposed to four different abiotic stress conditions, cold, heat (air), heat (water immersion), and salt, in the wild type Brachypodium cultivar Bd21. For our experiments we used information from the literature to select two time-points for stress durations, short and long, which differed for each stress: cold (6 and 24 hours), heat-air (1 and 3 hours), heat-water (1 and 3 hours), and salt (48 hours). We generated small RNA libraries for Illumina sequencing (GAII) from the leaves of Brachypodium plants subjected to stresses and selected smRNAs between 15 and 40 nt in length, which we mapped to the Brachypodium genome.

Dataset Information

Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron.

Publications

Transcriptional activation of the fra-1 gene by AP-1 is mediated by regulatory sequences in the first intron.

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