title: Pro-apoptotic Bim induction in response to nerve growth factor deprivation requires simultaneous activation of three different death signaling pathways.
abstract: Bim is a pro-apoptotic member of the Bcl-2 family that is induced and contributes to neuron death in response to nerve growth factor (NGF) deprivation. Past work has revealed that Bim is downstream of multiple independent transcriptional pathways in neurons, including those culminating in activation of the c-Jun, FoxO, and Myb transcription factors. This study addresses the issue of whether the three signaling pathways are redundant with respect to Bim induction or whether they act cooperatively. Examination of the proximal Bim promoter reveals binding sites for FoxO, Mybs, and, as shown here, c-Jun. We find that mutation of any one of these types of sites abolishes induction of a Bim promoter-driven reporter in response to NGF deprivation. Moreover, down-regulation of either c-Jun, FoxOs, or Mybs by short hairpin RNAs blocks induction of Bim promoter-reporter activity triggered by withdrawal of NGF. This was the case for reporters driven by either the proximal promoter or a promoter that also includes additional regulatory elements in the first intron of the Bim gene. Such short hairpin RNAs also suppressed the induction of endogenous Bim protein. These findings thus indicate that the Bim promoter acts as a coincidence detector that optimally responds to the simultaneous activation of three different pro-apoptotic transcriptional pathways. Such a mechanism provides a "fail-safe" that prevents neurons from dying by accidental activation of any single pathway. It also permits neurons to utilize individual pathways such as JNK signaling for other purposes without risk of demise.
authors: Department of Pathology, Center for Neurobiology and Behavior, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA. scb34@columbia.edu
authors: Subhas C
authors: SC
authors: Biswas
authors: Yijie
authors: Y
authors: Shi
authors: Andrew
authors: A
authors: Sproul
authors: Lloyd A
authors: LA
authors: Greene
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009154:Mutation; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D020598:Proto-Oncogene Proteins c-myb / Q000096:biosynthesis; D012313:RNA / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D051858:Forkhead Transcription Factors; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D020932:Nerve Growth Factor; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D020598:Proto-Oncogene Proteins c-myb; D012313:RNA; C000606778:Bcl2l11 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1