Tissue-Specific Transgenic Knockdown of Fos-Related Antigen 2 (Fra-2) Expression Mediated by Dominant Negative Fra-2

Abstract

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 Ͼ Ͼ Ͼ Ͼ 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).Fos-related antigen 2 (Fra-2) is a member of the Fos family of transcription factors (9,24,34

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

“…Fra2 was expected to be an inhibitory transcription factor involved in the decrease in Aa-nat mRNA in the morning MULTIPLE REGULATION OF PINEAL MELATONIN SYNTHESIS IN MAMMALS . However, this hypothesis is ruled out by the recent finding that pineal Aa-nat gene expression is not altered in transgenic rats with a dominant negative Fra2 gene (Smith et al, 2001). The daily AP-1 variation in the pineal gland is probably involved in some other transcriptional regulation.…”

Alterations in Fos-Related Antigen 2 and σ1 Receptor Gene and Protein Expression Are Associated with the Development of Cocaine-Induced Behavioral Sensitization: Time Course and Regional Distribution Studies

“…In earlier studies, calcium has been shown to be capable of inducing Fra-2 (Herdegen and Leah, 1998). Similar to other members of the fos family, Fra-2 is known to form heterodimeric complexes with other proteins, such as Jun and CREB family members (Herdegen and Leah, 1998;Smith et al, 2001). Moreover, Fra-2 can regulate the expression of other genes through interactions with the AP-1 DNA consensus element (Foletta, 1996;Boss et al, 2001).…”

“…These findings led to the hypothesis that cocaine may exert effects on IEGs, such as fra-2, which in turn alter the regulation of target late genes, one of which may be the 1 receptor. Because Fra-2 can form heterodimers with other transcription factors and bind to activator protein 1 (AP-1) sites (Herdegen and Leah, 1998;Smith et al, 2001), the presence of an AP-1 binding site on the 1 receptor promoter (Seth et al, 1997) suggested a mechanism through which the gene could be transcriptionally regulated. Subsequent cocaine-induced increases in 1 receptor expression may then lead to altered behavioral responses to later cocaine challenges, which can be expressed as sensitization.…”

Methionine Adenosyltransferase:Adrenergic-cAMP Mechanism Regulates a Daily Rhythm in Pineal Expression

“…In the pineal gland, cAMP treatment results in an elevation of c-Fos and Fos-related antigen-2, both of which bind to AP-1 sites. Either or both could mediate cAMP stimulation of MAT2A transcription (28,31).…”