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Nucleic Acids Research Advance Access published online on March 20, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp175
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

The proapoptotic dp5 gene is a direct target of the MLK-JNK-c-Jun pathway in sympathetic neurons

Emily Towers, Jonathan Gilley, Rebecca Randall, Rosie Hughes, Mark Kristiansen and Jonathan Ham*

Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK

*To whom correspondence should be addressed. Tel: +44 20 7905 2294; Fax: +44 20 7813 8100; Email: j.ham{at}ich.ucl.ac.uk

Received August 2, 2008. Revised March 1, 2009. Accepted March 3, 2009.

The death of sympathetic neurons after nerve growth factor (NGF) withdrawal requires de novo gene expression. Dp5 was one of the first NGF withdrawal-induced genes to be identified and it encodes a proapoptotic BH3-only member of the Bcl-2 family. To study how dp5 transcription is regulated by NGF withdrawal we cloned the regulatory regions of the rat dp5 gene and constructed a series of dp5-luciferase reporter plasmids. In microinjection experiments with sympathetic neurons we found that three regions of dp5 contribute to its induction after NGF withdrawal: the promoter, a conserved region in the single intron, and sequences in the 3' untranslated region of the dp5 mRNA. A construct containing all three regions is efficiently activated by NGF withdrawal and, like the endogenous dp5, its induction requires mixed-lineage kinase (MLK) and c-Jun N-terminal kinase (JNK) activity. JNKs phosphorylate the AP-1 transcription factor c-Jun, and thereby increase its activity. We identified a conserved ATF site in the dp5 promoter that binds c-Jun and ATF2, which is critical for dp5 promoter induction after NGF withdrawal. These results suggest that part of the mechanism by which the MLK-JNK-c-Jun pathway promotes neuronal apoptosis is by activating the transcription of the dp5 gene.

Present addresses: Emily Towers, Centre for Auditory Research, UCL Ear Institute, 332-336 Gray's Inn Road, London WC1X 8EE, UK Jonathan Gilley, Laboratory of Neuronal Development and Survival, The Babraham Institute, Cambridge CB2 4AT, UK Rebecca Randall, Developmental Signalling Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK


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