Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation

Abstract

Insulin regulates the activity of the AP-1 (activator protein-1) transcriptional complex in several cell types. One component of the AP-1 complex is the transcription factor Fra-1 (fos-related antigen-1), and we have demonstrated previously that insulin stimulates the expression of Fra-1 mRNA in CHO.T cells [Griffiths, Black, Culbert, Dickens, Shaw, Gillespie and Tavaré (1998) Biochem. J. 335, 19-26]. Here we demonstrate that insulin stimulates the activity of a fra-1 promoter linked to a luciferase reporter gene, indicating that the ability of insulin to induce expression of Fra-1 mRNA is due, at least in part, to an increase in gene transcription. Furthermore, we found that insulin induces the serine phosphorylation of Fra-1 and reduces its mobility during SDS/PAGE as a result of phosphorylation. The ability of insulin to induce the accumulation of Fra-1 mRNA, stimulate the fra-1 promoter and stimulate phosphorylation of Fra-1 all require the mitogen-activated protein (MAP) kinase cascade, which leads to the activation of extracellular-signal-regulated kinase (Erk) 1/2. Consequently, our results demonstrate that the Erk cascade plays a dual role in the co-ordinated regulation of the transcription and the phosphorylation of Fra-1 by insulin.

Mitogen regulated induction of FRA-1 proto-oncogene is controlled by the transcription factors binding to both serum and TPA response elements

“…Furthermore, Elk1 phosphorylation is tightly correlated with the activation of ERK1 and ERK2 MAP kinases following TPA and EGF treatment, and the inhibition of ERK Collectively, these results support a critical role for Elk1 in mediating SRE-dependent FRA-1 induction. These results are also in agreement with previous reports that showed an attenuation of mitogen-inducible FRA-1 mRNA expression by inhibitors of ERK signaling (Cook et al, 1999;Hurd et al, 2002;Ramos-Nino et al, 2002;Vial and Marshall, 2003). Based on data obtained from our current and previous studies (Adiseshaiah et al, 2003) and those of others (Bergers et al, 1995;Brusselbach et al, 1995;Schreiber et al, 1997), we propose the following model for the transcriptional induction of FRA-1 by mitogens, such as TPA (Figure 11).…”

A Phosphatidylinositol 3-Kinase-regulated Akt-Independent Signaling Promotes Cigarette Smoke-induced FRA-1 Expression

“…4A), which are essential for high level induction of FRA-1 by CS (25), tumor promoters, and mitogens in HBE cells (data not shown). Consistent with this, a prominent role for ERK signaling in mitogen-inducible FRA-1 mRNA expression has been shown in other cell types (17,(42)(43)(44). Although a requirement for PI3K pathway in mitogen-induced ERK activation has been suggested in other cells, the present study went further to demonstrate a link between CS-induced PI3K signaling and ERK activation for the first time in HBE cells (Fig.…”

FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells

“…Fra-1 is a target for sustained activation of the MAPK cascade (Cook et al, 1999). MAPK, which phosphorylates Fra-1 (Gruda et al, 1994;Cook et al, 1999;Hurd et al, 2002;Young et al, 2002), increases fra-1 gene transcription (Hurd et al, 2002) but also Fra-1 DNA-binding activity (Gruda et al, 1994) and may affect Fra-1 transcriptional activity (Young et al, 2002).…”