Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein
Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein
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DOI：
10.1006/bbrc.2001.5512
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发表时间：
2001-09-07
影响因子：
3.1
通讯作者：
Johnson, DE
中科院分区：
文献类型：
--
作者：
Antoku, K;Maser, RS;Johnson, DE
Bcl-2癌蛋白是一种有效的细胞凋亡抑制剂，在多种不同的恶性肿瘤中过表达。Bcl-2功能通过与Bcl-2蛋白家族的其他成员的异二聚化来调节。此外，一些不是Bcl-2家族成员的蛋白质可以与Bcl-2结合，包括BAG-1蛋白。在这项研究中，我们筛选了与Bcl-2结合的蛋白质，并分离出BAG-1蛋白家族的另外两个成员，BAG-3和BAG-4。我们克隆的BAG-4蛋白也对应于最近分离的死亡结构域抑制因子（SODD）蛋白，一种结合并抑制肿瘤坏死因子受体1（TNFR 1）信号传导的分子。发现BAG-3和BAG-4/SODD都与Bcl-2物理相关，并且这两种蛋白质从人到小鼠都很保守。在BAG-3和BAG-4/SODD的羧基末端存在一个包含68个氨基酸的同源区域，该区域与在BAG-1蛋白家族的其它成员中发现的称为BAG结构域的序列相对应。在BAG-3和BAG-4/SODD中，BAG结构域似乎构成这些分子的Bcl-2结合区。与BAG-1一样，BAG-3和BAG-4/SODD也显示与细胞内的Hsp 70结合。此外，BAG-3过表达适度抑制由IL-3依赖性320细胞的细胞因子剥夺引起的凋亡。总之，我们的研究结果表明，BAG-1蛋白家族的其他成员，即BAG-3和BAG-4/SODD，与Bcl-2结合，并在Bcl-2调节的途径与Hsp 70调节的途径之间提供了潜在的联系，以及TNFR 1。(C)北京：科学出版社.
The Bcl-2 oncoprotein is a potent inhibitor of apoptosis and is overexpressed in a variety of different malignancies. Bcl-2 function is regulated through heterodimerization with other members of the Bcl-2 protein family. In addition, several proteins that are not members of the Bcl-2 family can bind to Bcl-2, including BAG-1 protein. In this study, we screened for proteins that bind to Bcl-2, and isolated two additional members of the BAG-1 protein family, BAG-3 and BAG-4. The BAG-4 protein that we cloned also corresponds to the recently isolated suppressor of death domains (SODD) protein, a molecule that binds and inhibits signaling by tumor necrosis factor receptor 1 (TNFR1). Both BAG-3 and BAG-4/SODD were found to physically associate with Bcl-2, and both proteins are well conserved from human to mouse. A region of homology, comprising 68 amino acids, is present in the carboxyl termini of BAG-3 and BAG-4/SODD, and this region corresponds with sequences termed BAG domains that are found in other members of the BAG-1 protein family. In BAG-3 and BAG-4/SODD, the BAG domains appear to constitute the Bcl-2 binding regions of these molecules. BAG-3 and BAG-4/SODD, like BAG-1, were also shown to bind to Hsp70 inside the cell. Moreover, BAG-3 overexpression modestly inhibited apoptosis resulting from cytokine deprivation of IL-3-dependent 320 cells. Together, our findings demonstrate that other members of the BAG-1 protein family, namely BAG-3 and BAG-4/SODD, bind to Bcl-2 and provide a potential link between pathways regulated by Bcl-2 and pathways regulated by Hsp70, as well as TNFR1. (C) 2001 Academic Press.