Tissue-specific transgenic knockdown of Fos-related antigen 2 (Fra-2) expression mediated by dominant negative Fra-2.
Fos-related antigen 2 (Fra-2) is a member of the Fos family of immediate-early genes, most of which are rapidly induced by second messengers. All members of this family act by binding to AP-1 sites as heterodimeric complexes with other proteins. However, each appears to have a distinct role. The role and biology of Fra-2 are less well understood than those of its relatives c-Fos, Fra-1, and FosB; moreover, Fra-2 target genes remain largely unknown, as does the basis of its selective effects on transcriptional activity. To pursue these issues, we created a transgenic rat line (NATDNF2) in which a dominant negative fra-2 (DNF2) gene is strongly expressed in the pineal gland; tissue selectivity was achieved by putting the DNF2 gene under the control of the rat arylalkylamine N-acetyltransferase (AANAT) regulatory region, which targets gene expression to a very restricted set of tissues (pineal gland >> retina). Expression of AANAT is normally turned on after the onset of darkness in the rat; as a result, pineal DNF2 expression occurs only at night. This was associated with marked suppression of the nocturnal increase in fra-2 mRNA and protein levels, indicating that DNF2 expression inhibits downstream effects of Fra-2, including the maintenance of high levels of fra-2 gene expression. Analysis of 1,190 genes in the NATDNF2 pineal gland, including the AANAT gene, identified two whose expression is strongly linked to fra-2 expression: the genes encoding type II iodothyronine deiodinase and nectadrin (CD24).
Smith
M
M
School of Bioscience, Cardiff University, Cardiff, United Kingdom.
Burke
Z
Z
Humphries
A
A
Wells
T
T
Klein
D
D
Carter
D
D
Baler
R
R
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051921:Fos-Related Antigen-2; D015870:Gene Expression; D005786:Gene Expression Regulation; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008550:Melatonin / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010870:Pineal Gland / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011817:Rabbits; D051381:Rats; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; C497874:Fosl2 protein, rat; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D001191:Arylamine N-Acetyltransferase; D008550:Melatonin