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

Oncogene volume 25, pages 2974–2986 (2006)Cite this article

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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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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