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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.

Pubmed ID: 16434970

Authors

  • Han YH
  • Cao X
  • Lin B
  • Lin F
  • Kolluri SK
  • Stebbins J
  • Reed JC
  • Dawson MI
  • Zhang XK

Journal

Oncogene

Publication Data

May 18, 2006

Associated Grants

  • Agency: NCI NIH HHS, Id: CA109345
  • Agency: NCI NIH HHS, Id: CA87000
  • Agency: NIGMS NIH HHS, Id: GM60544

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