Evidence for increased complexity in the regulation of Bim expression in sympathetic neurons: Involvement of novel transcriptional and translational mechanisms

The BH3-only protein Bim is induced following NGF deprivation in developing sympathetic neurons and contributes to their death by apoptosis. The regulation of Bim activity is complex, and involves both transcriptional and posttranslational mechanisms. We have previously shown that both the FOXO subfamily of Forkhead transcription factors and the JNK/c-Jun pathway contribute to the transcriptional induction of Bim expression and subsequent apoptosis of sympathetic neurons following NGF deprivation. Bim activity can also be modulated by JNK-mediated phosphorylation after NGF deprivation in these cells. Here, we provide evidence for additional complexity in the transcriptional and translational control of Bim expression. We show that the first intron of the bim gene contains elements with silencer and enhancer properties that can modulate the basal activity and NGF deprivation-induced activity of the previously characterized bim promoter. Surprisingly, we find that some of the elements responsible for these effects are linked to two novel, alternative promoters located towards the 3' end of the intron that have minimal, or no activity in sympathetic neurons. Finally, we provide evidence that Bim expression is reduced in sympathetic neurons by the presence of an upstream open reading frame in the 5' leader of bim transcripts.