Microtubule disarray in primary cultures of human hepatocytes inhibits transcriptional activity of the glucocorticoid receptor via activation of c-jun N-terminal kinase.
The human glucocorticoid receptor (hGR) plays a pivotal role in cellular processes such as development, differentiation, homeostasis, immune response and in regulation of xenobiotic metabolism. It has been demonstrated recently that colchicine inhibits hGR transcriptional activity in primary cultures of human hepatocytes by a mechanism involving impairment of hGR nucleo-cytoplasmic shuttling. In the present work, we investigated the role of the nuclear factor kappa B (NFkappaB) and c-jun-N-terminal kinase (JNK), the functional hGR antagonists, in this process. We found that microtubule disarray caused by colchicine, vincristine or nocodazole does not activate NFkappaB in human hepatocytes as revealed by p50 and p65 subunits nuclear translocation. On the other hand, we demonstrate that JNK mediates hGR transcriptional inhibition by microtubules disarray, because a specific inhibitor of JNK, 1,9-pyrazoloanthrone (SP600125), partially blocked tyrosine aminotransferase mRNA suppression due to colchicine treatment. In conclusion, JNK is at least partly involved in hGR transcriptional inhibition by colchicine in human hepatocytes, while NFkappaB involvement is doubtful.
Dvorák
Zdenek
Z
Institute of Medical Chemistry and Biochemistry, Faculty of Medicine, Palacký University Olomouc, Hnevotínská 3, Olomouc 77515, Czech Republic. moulin@email.cz
Maurel
Patrick
P
Ulrichová
Jitka
J
Modrianský
Martin
M
D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D003078:Colchicine / Q000494:pharmacology; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure*; D016328:NF-kappa B / Q000378:metabolism / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects*; D014444:Tyrosine Transaminase / Q000378:metabolism
D000873:Anthracenes; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; C432165:pyrazolanthrone; D014444:Tyrosine Transaminase; D048031:JNK Mitogen-Activated Protein Kinases; D003078:Colchicine