TY - JOUR
T1 - Nuclear Ca2+ and CaM kinase IV specify hormonal- and Notch-responsiveness
AU - McKenzie, Grahame J.
AU - Stevenson, Patrick
AU - Ward, George
AU - Papadia, Sofia
AU - Bading, Hilmar
AU - Chawla, Sangeeta
AU - Privalsky, Martin
AU - Hardingham, Giles E.
PY - 2005/4
Y1 - 2005/4
N2 - Many neuronal processes require gene activation by synaptically evoked Ca2+ transients. Ca2+-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 Ca2+-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.
AB - Many neuronal processes require gene activation by synaptically evoked Ca2+ transients. Ca2+-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 Ca2+-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.
KW - Calcium signalling
KW - Calcium-calmodulin-dependent protein kinase
KW - Mitogen-activated protein kinases
KW - Nuclear hormone receptors
KW - SMRT
UR - http://www.scopus.com/inward/record.url?scp=16244362345&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=16244362345&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2005.03010.x
DO - 10.1111/j.1471-4159.2005.03010.x
M3 - Article
C2 - 15773917
AN - SCOPUS:16244362345
VL - 93
SP - 171
EP - 185
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 1
ER -