Human CCAAT/Enhancer-Binding Protein β Interacts with Chromatin Remodeling Complexes of the Imitation Switch Subfamily
Human CCAAT/Enhancer-Binding Protein β Interacts with Chromatin Remodeling Complexes of the Imitation Switch Subfamily
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DOI：
10.1021/bi201593q
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发表时间：
2012-02-07
期刊：
影响因子：
2.9
通讯作者：
Gutierrez, Jose L.
中科院分区：
文献类型：
--
作者：
Steinberg, Ximena P.;Hepp, Matias I.;Gutierrez, Jose L.
转录因子C/EBP β参与多种细胞过程，如增殖、分化和能量代谢。该因子通过招募不同的蛋白质或蛋白质复合物（包括ATP依赖性染色质重塑复合物SWI/SNF）来发挥其活性。C/EBP β蛋白被发现为三种主要的同种型，C/EBP β 1、-2和-3。它们通过在独特mRNA的替代AUG起始密码子处翻译产生，C/EBP β 1是全长同种型。研究发现C/EBP β 1参与终末分化过程。相反，C/EBP β 2和-3促进细胞增殖，并参与许多组织的恶性进展。C/EBP β 2和β 3促进细胞增殖和肿瘤进展的机制尚未完全了解。在这项工作中，我们试图使用蛋白质组学方法鉴定与hC/EBP β相互作用的蛋白质。我们发现，所有三种异构体与hSNF 2 H和hACF相互作用，ACF和CHRAC染色质重塑复合物的组分，属于模仿开关亚家族。其他蛋白质-蛋白质相互作用研究证实了这一发现，也表明hC/EBP β直接与hACF 1相互作用。通过在HepG 2细胞中过表达hC/EBP β、hSNF 2 H和hACF 1，并分析细胞周期蛋白D1和其他C/EBP β靶基因表达的变化，我们观察到C/EBP β和SNF 2 H/ACF 1之间的功能性相互作用，其特征主要是在SNF 2 H和ACF 1存在下抑制C/EBP β反式激活活性。与这些发现相一致，1%DMSO诱导HepG 2细胞分化伴随着细胞周期蛋白D1表达水平的降低以及hC/EBP β、hSNF 2 H和hACF 1在该基因启动子区的出现。
Transcription factor C/EBP beta is involved in several cellular processes, such as proliferation, differentiation, and energy metabolism. This factor exerts its activity through recruitment of different proteins or protein complexes, including the ATP-dependent chromatin remodeling complex SWI/SNF. The C/EBP beta protein is found as three major isoforms, C/EBP beta 1, -2, and -3. They are generated by translation at alternative AUG initiation codons of a unique mRNA, C/EBP beta 1 being the full-length isoform. It has been found that C/EBP beta 1 participates in terminal differentiation processes. Conversely, C/EBP beta 2 and -3 promote cell proliferation and are involved in malignant progression in a number of tissues. The mechanisms by which C/EBP beta 2 and -3 promote cell proliferation and tumor progression are not fully understood. In this work, we sought to identify proteins interacting with hC/EBP beta using a proteomics approach. We found that all three isoforms interact with hSNF2H and hACF, components of ACF and CHRAC chromatin remodeling complexes, which belong to the imitation switch subfamily. Additional protein-protein interaction studies confirmed this finding and also showed that hC/EBP beta directly interacts with hACF1. By overexpressing hC/EBP beta hSNF2H, and hACF1 in HepG2 cells and analyzing variations in expression of cyclin D1 and other C/EBP beta target genes, we observed a functional interaction between C/EBP beta and SNF2H/ACF1, characterized mainly by suppression of C/EBP beta transactivation activity in the presence of SNF2H and ACF1. Consistent with these findings, induction of differentiation of HepG2 cells by 1% DMSO was accompanied by a reduction in the level of cyclin D1 expression and the appearance of hC/EBP beta hSNF2H, and hACF1 on the promoter region of this gene.