Fra-1 substitutes for c-Fos in AP-1-mediated signal transduction in retinal apoptosis

Abstract

Lack of the AP-1 member c-Fos protects photoreceptors against light-induced apoptosis, a model for retinal degeneration. In mice, light damage increases the activity of the transcription factor AP-1, while pharmacological suppression of AP-1 prevents apoptosis, suggesting the involvement of pro-apoptotic AP-1 target genes. Recently, however, it was shown that photoreceptors expressing Fra-1 in place of c-Fos (FosFosl1/Fosl1) are apoptosis competent despite the lack of transactivation domains in Fra-1. Here, we show that morphological features of light-induced apoptosis were indistinguishable in FosFosl1/Fosl1 and wild-type mice. Furthermore, light exposure comparably increased AP-1 activity in both genotypes. Opposite to wild-type mice, Fra-1, but not c-Fos, was detectable in AP-1 complexes of FosFosl1/Fosl1 mice. Importantly, AP-1 responsiveness for glucocorticoid receptor-mediated inhibition was preserved in FosFosl1/Fosl1 mice. Thus, Fra-1 takes over for c-Fos in pro- and anti-apoptotic signal transduction. As Fra-1 lacks transactivation domains, AP-1 may not induce, but rather suppress genes in retinal light damage.