Journal of Biological Chemistry
Volume 282, Issue 2, 12 January 2007, Pages 1288-1295
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Mechanisms of Signal Transduction
Proapoptotic Nix Activates the JNK Pathway by Interacting with POSH and Mediates Death in a Parkinson Disease Model*

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Nix, a pro-apoptotic BH3-only protein, promotes apoptosis of non-neuronal cells, although the mechanisms involved remain incompletely understood. Using a yeast two-hybrid screen with POSH (plenty of SH3 domains, a scaffold involved in activation of the apoptotic JNK/c-Jun pathway) as the bait, we identified an interaction between POSH and Nix. Co-immunoprecipitation and in vitro binding studies confirmed a direct interaction between POSH and Nix in mammalian cells. When overexpressed in HEK293 cells, Nix promotes apoptosis along with enhanced phosphorylation/activation of JNKs and their target c-Jun. These effects appear to be dependent on POSH because Nix does not promote either JNK/c-Jun phosphorylation or apoptosis of 293 cells that do not express POSH. Nix and POSH appear to mutually stabilize one another and this effect could contribute to their promotion of death. Past work showed induction of Nix transcripts in a cellular model of Parkinson disease based on neuronal PC12 cells exposed to 6-hydroxydopamine. Here, we confirm elevation of Nix protein in this model and that Nix over-expression causes apoptotic death of PC12 cells by a mechanism dependent on c-Jun activation. Expression of s-Nix, a dominant-negative form of Nix, protects neuronal PC12 cells from 6-hydroxydopamine but not from nerve growth factor deprivation. These results indicate that Nix promotes cell death via interaction with POSH and activation of the JNK/c-Jun pathway and that Nix protein is induced and contributes to cell death in a cellular model of Parkinson disease.

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*

This work was supported by National Institutes of Health Grants 5RO1 NS033689 and 5PO1 NS38370-06 (to L. A. G.) and by 973 Program No. 2006CB504100/2006CB500701 (to Z. X.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

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Current address: Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.