Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5
Activation of the myocyte enhancer factor-2 transcription factor by calcium/calmodulin-dependent protein kinase-stimulated binding of 14-3-3 to histone deacetylase 5
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DOI：
10.1073/pnas.260501497
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发表时间：
2000-12-19
影响因子：
11.1
通讯作者：
Olson, EN
中科院分区：
文献类型：
--
作者：
McKinsey, TA;Zhang, CL;Olson, EN
骨骼肌分化是由肌细胞增强因子2（MEF 2）和生肌碱性螺旋-环-螺旋转录因子之间的相互作用控制的。MEF 2与组蛋白脱乙酰酶（HDAC）-4和-5的关联导致MEF 2靶基因的阻遏和肌生成的抑制。钙/钙调蛋白依赖性蛋白激酶（CaMK）信号传导通过破坏MEF 2-HDAC复合物并刺激HDAC核输出来促进肌生成。为了进一步确定赋予CaMK对HDAC 4和-5的反应性的机制，我们进行了酵母双杂交筛选以鉴定HDAC相互作用因子。这些筛选揭示了HDAC 4与14-3-3蛋白家族成员之间的相互作用，这些蛋白家族充当信号依赖性细胞内伴侣。HDAC 4在酵母和哺乳动物细胞中组成性结合14-3-3，而HDAC 5结合14-3-3在很大程度上依赖于CaMK信号传导。CaMK磷酸化HDAC 5中的丝氨酸-259和-498，其随后用作14-3-3的对接位点。我们的研究表明，14-3-3与HDAC 5的结合是MEF 2-HDAC复合物的CaMK依赖性破坏和HDAC 5的核输出所必需的，并暗示14-3-3是肌细胞分化的信号依赖性调节剂。
Skeletal muscle differentiation is controlled by interactions between myocyte enhancer factor-2 (MEF2) and myogenic basic helix-loop-helix transcription factors. Association of MEF2 with histone deacetylases (HDAC) -4 and -5 results in repression of MEF2 target genes and inhibition of myogenesis. Calcium/calmodulin-dependent protein kinase (CaMK) signaling promotes myogenesis by disrupting MEF2-HDAC complexes and stimulating HDAC nuclear export. To further define the mechanisms that confer CaMK responsiveness to HDAC4 and -5, we performed yeast two-hybrid screens to identify HDAC-interacting factors. These screens revealed interactions between HDAC4 and members of the 14-3-3 family of proteins, which function as signal-dependent intracellular chaperones. HDAC4 binds constitutively to 14-3-3 in yeast and mammalian cells, whereas HDAC5 binding to 14-3-3 is largely dependent on CaMK signaling. CaMK phosphorylates serines -259 and -498 in HDAC5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to HDAC5 is required for CaMK-dependent disruption of MEF2-HDAC complexes and nuclear export of HDAC5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.