AP-1 mediated retinal photoreceptor apoptosis is independent of N-terminalphosphorylation of c-Jun

Apoptosis is essential for retinal development but it is also a major mode of cell loss in many human retinal dystrophies. High levels of visible ligh t induce retinal apoptosis in mice and rats. This process is dependent on t he induction of the transcription factor AP-1, a dimeric complex composed o f c-Fos and c-Jun/JunD phosphoproteins. While c-Fos is essential, JunD is d ispensable for light-induced photoreceptor apoptosis. Here we show that N-t erminal phosphorylation of c-Jun, the other main partner of c-Fos in induce d AP-1 complexes is not required for programmed cell death during retinal d evelopment in vivo and is also dispensable for photoreceptor apoptosis indu ced by the exogenous stimuli 'excessive light' and N-nitroso-N-methylurea ( MNU), Mice expressing a mutant c-Jun protein (JunAA) that cannot be phospho rylated at its N-terminus are apoptosis competent and their retina is not d istinguishable from wild-type mice, Accordingly, Jun kinase, responsible fo r phosphorylation of wild-type c-Jun protein is at best only marginally ind uced by the apoptotic stimuli 'light' and MNU, Complex composition of light -induced AP-1 complexes is similar in wild-type and JunAA mice. This shows that the mutant c-Jun protein can be part of the DNA binding complex AP-1 a nd demonstrates that induction of the DNA binding activity of AP-I after li ght insult does not depend on N-terminal phosphorylation of c-Jun, Our resu lts suggest that transactivation of target genes by phosphorylated c-jun/AP -1 is not required for MNU- or light-induced apoptosis of photoreceptor cel ls.