Calcium/Calmodulin-dependent Protein Kinase Activates Serum Response Factor Transcription Activity by Its Dissociation from Histone Deacetylase, HDAC4

Abstract

Serum response factor (SRF) plays a pivotal role in cardiac myocyte development, muscle gene transcription, and hypertrophy. Previously, elevation of intracellular levels of Ca 2؉ was shown to activate SRF function without involving the Ets family of tertiary complex factors through an unknown regulatory mechanism. Here, we tested the hypothesis that the chromatin remodeling enzymes of class II histone deacetylases (HDAC4) regulate SRF activity in a Ca 2؉ -sensitive manner. Expression of HDAC4 profoundly repressed SRFmediated transcription in both muscle and nonmuscle cells. Protein interaction studies demonstrated physical association of HDAC4 with SRF in living cells. The SRF/ HDAC4 co-association was disrupted by treatment of cells with hypertrophic agonists such as angiotensin-II and a Ca 2؉ ionophore, ionomycin. Furthermore, activation of Ca 2؉ /calmodulin-dependent protein kinase (CaMK)-IV prevented SRF/HDAC4 interaction and derepressed SRF-dependent transcription activity. The SRF⅐HDAC4 complex was localized to the cell nucleus, and the activated CaMK-IV disrupted HDAC4/SRF association, leading to export of HDAC4 from the nucleus and stimulation of SRF transcription activity. Thus, these results identify SRF as a functional interacting target of HDAC4 and define a novel tertiary complex factor-independent mechanism for SRF activation by Ca 2؉ /CaMK-mediated signaling.

Synaptic activity-responsive element in the Arc / Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons

“…However, the discovery of a physical clustering, corequirement and sufficiency of the 3 activitydependent cis-regulatory elements located in such close proximity (Ϸ100 bp) in SARE is particularly striking, suggesting that SARE may have a unique role as a coincidence detector for the 3 activity-dependent transcription factors. Intriguingly, we observed that mutations in the SRF-binding site not only abolished SARE activation, but also significantly augmented basal activity under silenced conditions, suggesting an additional role of SRF for transcriptional repression as previously reported in certain contexts in nonneuronal cells (29).…”

HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF

“…Indeed, it has been speculated (Lemercier et al, 2002) that recruitment of class II HDACs to repress transcription could be a common mechanism for this family of proteins. Evidence is accumulating that class II HDACs help mediate the transcriptional repression of genes crucial for differentiation, as documented for the serum response factor (SRF) (Davis et al, 2003), MEF-2 in myogenesis McKinsey et al, 2000;Dressel et al, 2001), or GATA-1 in erythroid differentiation (Watamoto et al, 2003), and our results suggest that HDAC4 could play a key role in PLZF-mediated myeloid differentiation. Interestingly, in contrast to MEF-2, PLZF does not seem to interact with the N-terminal region of HDAC4.…”

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…As SRF and Etslike transcription factor 1 (Elk1), binding sites for which are present in Region-1, were previously reported to interact with HDACs (24,25), it is possible that Arc transcription is suppressed by HDAC-mediated repressive machinery. Therefore, we examined the effects of trichostatin A (TSA), an inhibitor of HDAC, on Arc expression.…”