title: Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness.
abstract: Many neuronal processes require gene activation by synaptically evoked Ca(2+) transients. Ca(2+)-dependent signal pathways activate some transcription factors outright, but here we report that such signals also potentiate the activation of nuclear receptors by their cognate hormone, and of CBF1 by Notch, transcription factors hitherto not thought to be Ca(2+)-responsive. This potentiation is occluded by histone deacetylase inhibition, indicating a mechanism involving inactivation of co-repressors associated with these transcription factors. Synaptic activity, acting via the nuclear Ca(2+)-dependent activation of CaM kinase IV, triggers the disruption of subnuclear domains containing class II histone deacetylases (HDACs) and silencing mediator of retinoic acid and thyroid hormone receptors (SMRT), a broad-specificity co-repressor which represses nuclear hormone receptors and CBF1. The sequential loss of class II HDACs and SMRT from the subnuclear domains, followed by nuclear export, is associated with disruption of SMRT interaction with its target transcription factors and sensitization of these factors to their activating signal. Counterbalancing these changes, protein phosphatase 1 promotes nuclear localization of SMRT and inactivation of nuclear receptors and CBF1. Thus, the synaptically controlled kinase-phosphatase balance of the neuron determines the efficacy of SMRT-mediated repression and the signal-responsiveness of a variety of transcription factors.
authors.affiliation: Lorantis Ltd, Cambridge, UK.
authors.forename: Grahame J
authors.initials: GJ
authors.lastname: McKenzie
authors.forename: Patrick
authors.initials: P
authors.lastname: Stevenson
authors.forename: George
authors.initials: G
authors.lastname: Ward
authors.forename: Sofia
authors.initials: S
authors.lastname: Papadia
authors.forename: Hilmar
authors.initials: H
authors.lastname: Bading
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Chawla
authors.forename: Martin
authors.initials: M
authors.lastname: Privalsky
authors.forename: Giles E
authors.initials: GE
authors.lastname: Hardingham
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003952:Diagnostic Imaging; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006655:Histone Deacetylases / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2; D019319:Okadaic Acid / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051880:Receptors, Notch; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection / Q000379:methods; D014212:Tretinoin / Q000494:pharmacology; D014966:Xanthenes / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D006728:Hormones; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D056985:Nuclear Receptor Co-Repressor 2; D026902:Potassium Channel Blockers; D011500:Protein Synthesis Inhibitors; D051880:Receptors, Notch; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D014966:Xanthenes; D049452:Green Fluorescent Proteins; D019319:Okadaic Acid; C059715:Fluo-3; C012589:trichostatin A; D014212:Tretinoin; D015761:4-Aminopyridine; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D006655:Histone Deacetylases; D002118:Calcium; D001640:Bicuculline