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Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt

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Abstract

Proapoptotic nuclear receptor family member Nur77 translocates from the nucleus to the mitochondria, where it interacts with Bcl-2 to trigger apoptosis. Nur77 translocation is induced by certain apoptotic stimuli, including the synthetic retinoid-related 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalenecarboxylic acid (AHPN)/CD437 class. In this study, we investigated the molecular mechanism by which AHPN/CD437 analog (E)-4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces Nur77 nuclear export. Our results demonstrate that 3-Cl-AHPC effectively activated Jun N-terminal kinase (JNK), which phosphorylates Nur77. Inhibition of JNK activation by a JNK inhibitor suppressed 3-Cl-AHPC-induced Nur77 nuclear export and apoptosis. In addition, several JNK upstream activators, including the phorbol ester TPA, anisomycin and MAPK kinase kinase-1 (MEKK1), phosphorylated Nur77 and induced its nuclear export. However, Nur77 phosphorylation by JNK, although essential, was not sufficient for inducing Nur77 nuclear export. Induction of Nur77 nuclear export by MEKK1 required a prolonged MEKK1 activation and was attenuated by Akt activation. Expression of constitutively active Akt prevented MEKK1-induced Nur77 nuclear export. Conversely, transfection of dominant-negative Akt or treatment with a phosphatidylinositol 3-kinase (PI3-K) inhibitor accelerated MEKK1-induced Nur77 nuclear export. Furthermore, mutation of an Akt phosphorylation residue Ser351 in Nur77 abolished the effect of Akt or the PI3-K inhibitor. Together, our results demonstrate that both activation of JNK and inhibition of Akt play a role in translocation of Nur77 from the nucleus to the cytoplasm.

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Acknowledgements

We thank L Frazer for preparation of the manuscript, Dr Steven Frisch for providing MEKK1 expression plasmids, Dr Dan Mercola for DN-JNK, Dr Thomas Mustelin for CA-Akt, and Dr Anning Lin for JNKK2-JNK1. This work is, in part, supported by grants to X-k Zhang, MI Dawson and JC Reed from the National Institutes of Health (CA87000, CA, GM60544, CA109345) and to X-k Zhang from the Susan G Komen Breast Cancer Foundation, the US Army Medical Research and Material Command, the California Tobacco-Related Diseases Research Program and the California Breast Cancer Research Program.

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  1. Burnham Institute for Medical Research, Cancer Center, La Jolla, CA, USA

    Y-H Han, X Cao, B Lin, F Lin, S K Kolluri, J Stebbins, J C Reed, M I Dawson & X-k Zhang

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  1. Y-H Han
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  2. X Cao
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  3. B Lin
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Han, YH., Cao, X., Lin, B. et al. Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt. Oncogene 25, 2974–2986 (2006). https://doi.org/10.1038/sj.onc.1209358

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