Regulation of Nur77 nuclear export by c-Jun N-terminal kinase and Akt.
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.
Mesh Terms:
Adamantane, Anisomycin, Apoptosis, Cell Line, Tumor, Cell Nucleus, Cinnamates, DNA-Binding Proteins, Enzyme Activation, Flavonoids, Humans, Imidazoles, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 7, MAP Kinase Kinase Kinase 1, Mutagenesis, Site-Directed, Nuclear Receptor Subfamily 4, Group A, Member 1, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Processing, Post-Translational, Protein Transport, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Pyridines, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Recombinant Fusion Proteins, Tetradecanoylphorbol Acetate, Transcription Factors
Adamantane, Anisomycin, Apoptosis, Cell Line, Tumor, Cell Nucleus, Cinnamates, DNA-Binding Proteins, Enzyme Activation, Flavonoids, Humans, Imidazoles, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 7, MAP Kinase Kinase Kinase 1, Mutagenesis, Site-Directed, Nuclear Receptor Subfamily 4, Group A, Member 1, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Processing, Post-Translational, Protein Transport, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Pyridines, Receptors, Cytoplasmic and Nuclear, Receptors, Steroid, Recombinant Fusion Proteins, Tetradecanoylphorbol Acetate, Transcription Factors
Oncogene
Date: May. 18, 2006
PubMed ID: 16434970
View in: Pubmed Google Scholar
Download Curated Data For This Publication
144718
Switch View:
- Interactions 3