Transactivation of Fra-1 and Consequent Activation of AP-1 Occur Extracellular Signal-Regulated Kinase Dependently

Abstract

Mitogen-activated protein (MAP) kinase, extracellular-signal-regulated kinases (ERKs) play an important role in activating AP-1-dependent transcription. Studies using the JB6 mouse epidermal model and a transgenic mouse model have established a requirement for AP-1-dependent transcription in tumor promotion. Tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor induce activator protein 1 (AP-1) activity and neoplastic transformation in JB6 transformation-sensitive (P ؉ ) cells, but not in transformation-resistant (P ؊ ) variants. The resistance in one of the P ؊ variants can be attributed to the low levels of the MAP kinases, ERKs 1 and 2, and consequent nonresponsiveness to AP-1 activation. The resistant variant is not deficient in c-fos transcription. The purpose of these studies was to define the targets of activated ERK that lead to AP-1 transactivation. The results establish that the transactivation domain of Fra-1 can be activated, that activation of Fra-1 is ERK dependent, and that a putative ERK phosphorylation site must be intact for activation to occur. Fra-1 was activated by TPA in ERK-sufficient P ؉ cells but not in ERK-deficient P ؊ cells. A similar activation pattern was seen for c-Fos but not for Fra-2. Gel shift analysis identified Fra-1 as distinguishing mitogen-activated (P ؉ ) from nonactivated (P ؊ ) AP-1 complexes. A second AP-1-nonresponsive P ؊ variant that underexpresses Fra-1 gained AP-1 response upon introduction of a Fra-1 expression construct. These observations suggest that ERK-dependent activation of Fra-1 is required for AP-1 transactivation in JB6 cells.

A 19S proteasomal subunit cooperates with an ERK MAPK-regulated degron to regulate accumulation of Fra-1 in tumour cells

“…Treatment of the cells with the mitogen TPA to induce phosphorylation and activation of Fra-1 (Young et al, 2002) did not alter the abundance of Fra-1/TBP-1 complexes. However, TBP-1 immunoprecipitates contained Fra-1 species of differing mobilities on SDS-polyacrylamide gel electrophoresis gels, a likely indication that multiple phosphorylation states of the protein were present .…”

Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development

“…In line with this notion, recent studies have shown that the AP-1 family member Fra-1 (Fosl1) is essential for efficient neoplastic transformation of keratinocytes (Young et al, 2002), whereas expression of the membrane-bound metalloproteinase Adam8 was recently correlated with lung cancer (Ishikawa et al, 2004). Coregulation of genes exposed by the SOM algorithm provides a basis for the identification of new concepts of transcriptional regulation and important transcription factors necessary for tumour promotion and progression into malignant tumour stages.…”

AP-1 dimers regulate transcription of the p14/p19ARF tumor suppressor gene

“…To test this hypothesis, we examined the effect of ERK inhibition on the induction of the p19 ARF promoter. Fra-1-containing dimers were shown to be phosphorylated by the ERK kinase pathway (Young et al, 2002). The inhibition of ERK using the U0126 drug significantly reduced induction of the p19 ARF promoter by the c-JunBFra-1 dimer, suggesting that ERK activity is essential for AP-1 regulation of the ARF gene (Figure 5e).…”