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Martina Minisini Eros Di
Giorgio Emanuela Kerschbamer Emiliano Dalla Massimo Faggiani Elisa Franforte Franz-Josef Meyer-Almes Rino Ragno Lorenzo Antonini Antonello Mai Francesco Fiorentino Dante Rotili Monica Chinellato Stefano Perin Laura Cendron Christian
X Weichenberger Alessandro Angelini Claudio Brancolini 《Nucleic acids research》2022,50(5):2566
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《Bioorganic & medicinal chemistry》2019,27(22):115087
Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted. 相似文献
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New role for hPar-1 kinases EMK and C-TAK1 in regulating localization and activity of class IIa histone deacetylases
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Dequiedt F Martin M Von Blume J Vertommen D Lecomte E Mari N Heinen MF Bachmann M Twizere JC Huang MC Rider MH Piwnica-Worms H Seufferlein T Kettmann R 《Molecular and cellular biology》2006,26(19):7086-7102
Class IIa histone deacetylases (HDACs) are found both in the cytoplasm and in the nucleus where they repress genes involved in several major developmental programs. In response to specific signals, the repressive activity of class IIa HDACs is neutralized through their phosphorylation on multiple N-terminal serine residues and 14-3-3-mediated nuclear exclusion. Here, we demonstrate that class IIa HDACs are subjected to signal-independent nuclear export that relies on their constitutive phosphorylation. We identify EMK and C-TAK1, two members of the microtubule affinity-regulating kinase (MARK)/Par-1 family, as regulators of this process. We further show that EMK and C-TAK1 phosphorylate class IIa HDACs on one of their multiple 14-3-3 binding sites and alter their subcellular localization and repressive function. Using HDAC7 as a paradigm, we extend these findings by demonstrating that signal-independent phosphorylation of the most N-terminal serine residue by the MARK/Par-1 kinases, i.e., Ser155, is a prerequisite for the phosphorylation of the nearby 14-3-3 site, Ser181. We propose that this multisite hierarchical phosphorylation by a variety of kinases allows for sophisticated regulation of class IIa HDACs function. 相似文献
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Cardiac hypertrophy is a form of global remodeling, although the initial step
seems to be an adaptation to increased hemodynamic demands. The characteristics
of cardiac hypertrophy include the functional reactivation of the arrested fetal
gene program, where histone deacetylases (HDACs) are closely linked in the
development of the process. To date, mammalian HDACs are divided into four
classes: I, II, III, and IV. By structural similarities, class II HDACs are then
subdivided into IIa and IIb. Among class I and II HDACs, HDAC2, 4, 5, and 9 have
been reported to be involved in hypertrophic responses; HDAC4, 5, and 9 are
negative regulators, whereas HDAC2 is a pro-hypertrophic mediator. The molecular
function and regulation of class IIa HDACs depend largely on the
phosphorylation-mediated cytosolic redistribution, whereas those of HDAC2 take
place primarily in the nucleus. In response to stresses, posttranslational
modification (PTM) processes, dynamic modifications after the translation of
proteins, are involved in the regulation of the activities of those
hypertrophy-related HDACs. In this article, we briefly review 1) the activation
of HDAC2 in the development of cardiac hypertrophy and 2) the PTM of HDAC2 and
its implications in the regulation of HDAC2 activity. [BMB Reports 2015; 48(3):
131-138] 相似文献
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A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase 总被引:1,自引:0,他引:1
Lauren Monovich Richard B. Vega Karl Miranda Michael Capparelli Dillon Phan Joseph A. Chapo Timothy A. McKinsey 《FEBS letters》2010,584(3):631-4187
Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase. 相似文献
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Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity 总被引:3,自引:0,他引:3
Schuetz A Min J Allali-Hassani A Schapira M Shuen M Loppnau P Mazitschek R Kwiatkowski NP Lewis TA Maglathin RL McLean TH Bochkarev A Plotnikov AN Vedadi M Arrowsmith CH 《The Journal of biological chemistry》2008,283(17):11355-11363
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To clarify the role of HDACs in erythropoiesis, expression, activity and function of class I (HDAC1, HDAC2, HDAC3) and class IIa (HDAC4, HDAC5) HDACs during in vitro maturation of human erythroblasts were compared. During erythroid maturation, expression of HDAC1, HDAC2 and HDAC3 remained constant and activity and GATA1 association (its partner of the NuRD complex), of HDAC1 increased. By contrast, HDAC4 content drastically decreased and HDAC5 remained constant in content but decreased in activity. In erythroid cells, pull down experiments identified the presence of a novel complex formed by HDAC5, GATA1, EKLF and pERK which was instead undetectable in cells of the megakaryocytic lineage. With erythroid maturation, association among HDAC5, GATA1 and EKLF persisted but levels of pERK sharply decreased. Treatment of erythroleukemic cells with inhibitors of ERK phosphorylation reduced by >90% the total and nuclear content of HDAC5, GATA1 and EKLF, suggesting that ERK phosphorylation is required for the formation of this complex. Based on the function of class IIa HDACs as chaperones of other proteins to the nucleus and the erythroid-specificity of HDAC5 localization, this novel HDAC complex was named nuclear remodeling shuttle erythroid (NuRSERY). Exposure of erythroid cells to the class II-selective HDAC inhibitor (HDACi) APHA9 increased γ/(γ+β) globin expression ratios (Mai et al., 2007), suggesting that NuRSERY may regulate globin gene expression. In agreement with this hypothesis, exposure of erythroid cells to APHA9 greatly reduced the association among HDAC5, GATA1 and EKLF. Since exposure to APHA9 did not affect survival rates or p21 activation, NuRSERY may represent a novel, possibly less toxic, target for epigenetic therapies of hemoglobinopaties and other disorders. 相似文献