cAMP-dependent proteolysis of GATA-6 is linked to JNK-signaling pathway.
A JNK inhibitor SP600125 inhibited cAMP-dependent proteolysis of GATA-6 by proteasomes around its IC50. We further examined the effects of SP600125 on the degradation of GATA-6 in detail, since an activator of JNK (anisomycin) is available. Interestingly, anisomycin immediately stimulated the export of nuclear GATA-6 into the cytoplasm, and then the cytoplasmic content of GATA-6 decreased slowly through degradation by proteasomes. Such an effect of anisomycin was inhibited by SP600125, indicating that the observed phenomenon might be linked to the JNK signaling pathway. The inhibitory effect of SP600125 could not be ascribed to the inhibition of PKA, since phosphorylation of CREB occurred in the presence of dbcAMP and SP600125. The nuclear export of GATA-6 was inhibited by leptomycin B, suggesting that CRM1-mediated export could be activated by anisomycin. Furthermore, it seems likely that the JNK activated by anisomycin may stimulate not only the nuclear export of GATA-6 through CRM1 but also the degradation of GATA-6 by cytoplasmic proteasomes. In contrast, A-kinase might activate only the latter process through JNK.
Department of Molecular Biology, School of Pharmacy, Iwate Medical University, 2-1-1, Nishitokuta, Yahaba, Shiwagun, Iwate 028-3694, Japan.
Hironori
H
Ushijima
Masatomo
M
Maeda
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D050993:GATA6 Transcription Factor / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D059748:Proteolysis; D051381:Rats
D000873:Anthracenes; D000903:Antibiotics, Antineoplastic; D005231:Fatty Acids, Unsaturated; D050993:GATA6 Transcription Factor; C084364:Gata6 protein, rat; C432165:pyrazolanthrone; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; C038753:leptomycin B