Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5
Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPβ by GCN5
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DOI：
10.1073/pnas.0607378104
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发表时间：
2007-02-20
影响因子：
11.1
通讯作者：
Hache, Robert J. G.
中科院分区：
文献类型：
--
作者：
Wiper-Bergeron, Nadine;Salem, Houssein Abdou;Hache, Robert J. G.
培养中的前脂肪细胞分化是由胰岛素和cAMP依赖的转录级联驱动的，该级联诱导bzip转录因子C/EBP β和C/EBP δ。我们之前的研究表明，糖皮质激素治疗强烈增强了这种分化途径，刺激了C/EBP β的协同抑制因子组蛋白去乙酰化酶1 （HDAC1）的滴定。这导致C/EBP α启动子的C/EBP β依赖性转录的显著增强，同时伴有前脂肪细胞分化的增强。在这里，我们发现C/EBP β被GCN5和PCAF在氨基酸98-102之间的赖氨酸残基簇内乙酰化，并且这种乙酰化是由糖皮质激素处理强烈诱导的。C/EBP β乙酰化基序内赖氨酸残基的精氨酸替代阻止了乙酰化，并阻断了糖皮质激素增强C/EBP β定向转录和增强C/EBP β依赖的前脂肪细胞分化的能力。此外，C/EBP β的乙酰化似乎直接干扰了HDAC1与C/EBP β的相互作用，这表明PCAF/ gcn5依赖性C/EBP β的乙酰化是决定该转录因子转录调控潜力的重要分子开关。
Preadipocyte differentiation in culture is driven by an insulin and cAMP dependant transcriptional cascade which induces the bzip transcription factors C/EBP beta and C/EBP delta. We have previously shown that glucocorticoid treatment, which strongly potentiates this differentiation pathway, stimulates the titration of the corepressor histone deacetylase 1 (HDAC1) from C/EBP beta. This results in a dramatic enhancement of C/EBP beta-dependent transcription from the C/EBP alpha promoter, concomitant with potentiation of preadipocyte differentiation. Here, we show that C/EBP beta is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98-102 and that this acetylation is strongly induced by glucocorticoid treatment. Arginine substitution of the lysine residues within the acetylation motif of C/EBP beta prevented acetylation and blocked the ability of glucocorticoids to enhance C/EBP beta-directed transcription and to potentiate C/EBP beta-dependent preadipocyte differentiation. Moreover, acetylation of C/EBP beta appeared to directly interfere with the interaction of HDAC1 with C/EBP beta, suggesting that PCAF/GCN5-dependent acetylation of C/EBP beta serves as an important molecular switch in determining the transcriptional regulatory potential of this transcription factor.