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The MEK-ERK pathway negatively regulates bim expression through the 3' UTR in sympathetic neurons

Hughes, R; Gilley, J; Kristiansen, M; Ham, J; (2011) The MEK-ERK pathway negatively regulates bim expression through the 3' UTR in sympathetic neurons. BMC Neuroscience , 12 , Article 69. 10.1186/1471-2202-12-69. Green open access

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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.

Type: Article
Title: The MEK-ERK pathway negatively regulates bim expression through the 3' UTR in sympathetic neurons
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/1471-2202-12-69
Publisher version: http://dx.doi.org/10.1186/1471-2202-12-69
Language: English
Additional information: © 2011 Hughes et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: BH3-ONLY PROTEIN BIM(EL), PROAPOPTOTIC ACTIVITY, GENE-EXPRESSION, KINASE PATHWAY, APOPTOSIS, PHOSPHORYLATION, SURVIVAL, PROMOTES, FAMILY, TARGET
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1319807
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