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

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.

Jun NH 2 -terminal kinase (JNK) prevents nuclear β-catenin accumulation and regulates axis formation in Xenopus embryos

“…(Magnifications: B-D, ϫ4,000. ) ptotic protein Nur77 from the nucleus (28,29). Consistent with this possibility, JNK protein is concentrated in the nucleus of Xenopus embryos (Fig.…”

“…It has been shown that JNK induces nuclear export of PDX-1 and Nur77 (28,29). A recent study also showed that JNK phosphorylates Nup214, a subunit of the nuclear pore complex (31).…”

A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

“…Western Blotting-Cell lysates were boiled in SDS sample buffer, resolved by SDS-PAGE (8 or 12.5% polyacrylamide), and transferred to nitrocellulose (35,36,41). After transfer, the membranes were blocked in 5% milk in TBST (10 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 0.05% Tween 20) for 30 min and incubated with primary antibody in 5% milk in TBST for 2 h at room temperature.…”

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

“…TR3 is a hyperphosphorylated protein that can be phosphorylated by a number of protein kinases including ERK2 (Katagiri et al, 2000;Slagsvold et al, 2002;Jacobs et al, 2004) and JNK1 (Kolluri et al, 2003;Han et al, 2006;Liu et al, 2007). Several studies have highlighted the importance of the ERK signal pathway in controlling TR3 translocation (Katagiri et al, 2000;Jacobs et al, 2004).…”