Zinc and the cytoskeleton in the neuronal modulation of transcription factor NFAT.
Transcription factor NFAT is crucial in the development of the nervous system due to its role in neuronal plasticity and survival. In this study we characterized the role of zinc and the cytoskeleton in the modulation of NFAT in neuronal cells. The incubation of cells in zinc deficient media led to NFAT activation that was inhibited by the calcium chelator BAPTA and the antioxidants (+/-)-alpha-lipoic acid and N-acetyl cysteine, suggesting the involvement of calcium and oxidants in the initial steps of NFAT activation associated with zinc deficiency. At a second step of regulation, a decrease in cellular zinc led to an impaired transport of the active NFAT from the cytosol into the nucleus due to alterations in tubulin polymerization secondary to a decrease in neuronal zinc. Furthermore, disruption of the cytoskeleton structure by cold and chemical agents (colchicine (Col), vinblastine (VB), cytochalasin D (Cyt)) also inhibited NFAT transport into the nucleus. The altered nuclear transport caused a decrease in NFAT-dependent gene expression. This study demonstrates for the first time that zinc can modulate transcription factor NFAT in neuronal cells, and that microtubules are involved in NFAT nuclear translocation, crucial event in the regulation of NFAT transcriptional activity.
Mackenzie
Gerardo G
GG
Department of Nutrition, University of California, Davis, Davis California, USA.
Oteiza
Patricia I
PI
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism; D016716:PC12 Cells; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
D000975:Antioxidants; D065095:Calcineurin Inhibitors; D002614:Chelating Agents; D050778:NFATC Transcription Factors; D016877:Oxidants; D050257:Tubulin Modulators; D016572:Cyclosporine; D004247:DNA; D019703:Calcineurin; D015032:Zinc; D002118:Calcium