Difference in transcriptional regulatory function between c-Fos and Fra-2

Abstract

Fra-2, one of the Fos-related antigens, is promptly expressed after the growth stimulation of fibroblasts, but its induction peak is later than that of c-Fos. In this report, we examined biochemical properties of Fra-2 and compared them with those of two other Fos family proteins, c-Fos and Fra-1. Like c-Fos and Fra-1, Fra-2 formed stable heterodimers with c-Jun, JunB or JunD in vitro and all these complexes had specific DNA-binding activity to AP-1-binding sites (AP-1 sites) or related sequences. When transiently introduced into a mouse embryonic carcinoma cell line, F9, with reporter genes containing the AP-1 site from the collagenase gene, fra-2 plus c-jun suppressed the transactivation by c-jun alone. This property of Fra-2 is in clear contrast to that of c-Fos, which stimulates the transcriptional activity of c-Jun by forming a stable heterodimer. Analysis of chimeric proteins between c-Fos and Fra-2 indicated that this difference is mainly attributable to their C terminal-half regions. Interestingly, this suppressive effect of Fra-2 was not observed in the combination with JunD: fra-2 plus junD, like c-fos plus junD, had higher transcriptional activity than junD alone. Fra-1 showed essentially the same transcriptional regulatory properties as Fra-2. These differential properties greatly expand the potential range of regulatory functions of the Fos family proteins.

Opposing activities of c-Fos and Fra-2 on AP-1 regulated transcriptional activity in mouse keratinocytes induced to differentiate by calcium and phorbol esters

“…Our transcriptional assays indicate that the Fra-2/ Jun B heterodimer is a powerful negative transcriptional regulator in keratinocytes, ®ndings that are consistent with previous reports (Sonobe et al, 1995;Suzuki et al, 1991). Down-regulation of transcriptional activity by the Fra-2/Jun B heterodimer in granular layer cells could serve a variety of purposes during the formation of normal skin.…”

“…For example, c-Fos can both activate and repress transcription (Gius et al, 1990), the full-length Fos B is a transcriptional activator (Dobrazanski et al, 1991) and a naturally occurring short form of Fos B inhibits AP-1 transactivation (Yen et al, 1991;Nakabeppu and Nathans, 1991). The Fos-related antigens Fra-1 and Fra-2 lack functional transactivation domains and are poor transcriptional activators (Gius et al, 1990;Yoshioka et al, 1995;Suzuki et al, 1991).…”

Transformation by ras modifies AP1 composition and activity

“…Increased levels of cJun and Fra1 will result also in enhanced transcriptional activation of AP1 target genes. Since cJun-Fra1 heterodimers are strong activators of a canonical TRE element (Suzuki et al, 1991;L Bakiri, personal communication).…”

“…AP1 recognition sequences are found in many promoters and enhancers of cellular and viral genes, including Collagenase, Stromelysin, Metallothionein IIA, Interleukin 2, Transforming Growth Factor b, Simian Virus 40, Polyomavirus and Papillomavirus. The di erent AP1 dimers exhibit similar DNA binding speci®cities but di er in their transactivation e ciencies Hirai et al, 1990;Suzuki et al, 1991). The binding a nities for di erent dimer combinations is dependent on the speci®c TRE sequence and on the promoter context (Halazonetis et al, 1988;Ryseck and Bravo, 1991).…”

Structure and chromosomal assignment of the mouse fra-1 gene, and its exclusion as a candidate gene for oc (osteosclerosis)

“…Fra-1 exhibits oncogenic potential similar to, but weaker than that of c-Fos, since overexpression in established rat ®broblasts leads to anchorage-independent growth and tumor development in athymic mice (Bergers et al, 1995). However, unlike c-Fos, Fra-1 lacks a transactivation domain and the entire Fra-1 protein fused to the DNA-binding domain of Gal4 was shown to lack any transcriptional activation function (Suzuki et al, 1991;Wisdom and Verma, 1993;Bergers et al, 1995). Therefore, fra-1 can not only increase, but also repress total AP-1 activity depending on the status of the other Fos proteins in the cell (Suzuki et al, 1991;Groskopf and Linzer, 1994;Bergers et al, 1995;Welter et al, 1995;Yoshioka et al, 1995).…”