title: The MEK-ERK pathway negatively regulates bim expression through the 3' UTR in sympathetic neurons.
abstract: BACKGROUND
  Apoptosis plays a critical role during neuronal development and disease. Developing sympathetic neurons depend on nerve growth factor (NGF) for survival during the late embryonic and early postnatal period and die by apoptosis in its absence. The proapoptotic BH3-only protein Bim increases in level after NGF withdrawal and is required for NGF withdrawal-induced death. The regulation of Bim expression in neurons is complex and this study describes a new mechanism by which an NGF-activated signalling pathway regulates bim gene expression in sympathetic neurons.
  
  
  RESULTS
  We report that U0126, an inhibitor of the prosurvival MEK-ERK pathway, increases bim mRNA levels in sympathetic neurons in the presence of NGF. We find that this effect is independent of PI3-K-Akt and JNK-c-Jun signalling and is not mediated by the promoter, first exon or first intron of the bim gene. By performing 3' RACE and microinjection experiments with a new bim-LUC+3'UTR reporter construct, we show that U0126 increases bim expression via the bim 3' UTR. We demonstrate that this effect does not involve a change in bim mRNA stability and by using PD184352, a specific MEK1/2-ERK1/2 inhibitor, we show that this mechanism involves the MEK1/2-ERK1/2 pathway. Finally, we demonstrate that inhibition of MEK/ERK signalling independently reduces cell survival in NGF-treated sympathetic neurons.
  
  
  CONCLUSIONS
  These results suggest that in sympathetic neurons, MEK-ERK signalling negatively regulates bim expression via the 3' UTR and that this regulation is likely to be at the level of transcription. This data provides further insight into the different mechanisms by which survival signalling pathways regulate bim expression in neurons.
authors.affiliation: Molecular Haematology and Cancer Biology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N1EH, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Hughes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.forename: Mark
authors.initials: M
authors.lastname: Kristiansen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ham
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins