β-catenin interacts with the FUS proto-oncogene product and regulates pre-mRNA splicing
β-catenin interacts with the FUS proto-oncogene product and regulates pre-mRNA splicing
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DOI：
10.1053/j.gastro.2005.07.025
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发表时间：
2005-10-01
期刊：
影响因子：
29.4
通讯作者：
Yamada, T
中科院分区：
文献类型：
--
作者：
Sato, S;Idogawa, M;Yamada, T
背景和目标：β-连环蛋白是Writ信号传导途径的下游效应物，并被认为通过激活T细胞因子（TCF）/淋巴增强因子（LEF）家族转录因子来发挥其致癌功能。然而，它仍然是不确定的β-连环蛋白的各种影响是否是由异常的基因反式激活引起的。在这项研究中，我们使用了蛋白质组学的方法，以获得进一步了解核β-连环蛋白的功能特性。研究方法：使用免疫沉淀和质谱法鉴定了来自结直肠癌细胞系DLD-1的核提取物中的天然含β-连环蛋白复合物的蛋白质组装。结果：β-连环蛋白与融合蛋白（FUS）和各种RNA结合蛋白发生物理相互作用/在脂肪肉瘤（TLS）中移位。FUS/TLS的表达与β-catenin的积聚和肠上皮细胞的未分化状态密切相关。FUS的瞬时转染抑制了β-连环蛋白诱发的TCF/LEF的基因反式激活，β-连环蛋白转染影响了E1 A小基因的剪接模式，并诱导了一种新的雌激素受体（ER）-β的剪接变体，发挥显性负活性。结论：人类癌症表达多种可变剪接的信使RNA（mRNA），但负责癌症相关可变剪接的精确分子机制在很大程度上是未知的。在这项研究中，我们证明了β-连环蛋白与FUS/TLS和其他RNA结合蛋白的相互作用，参与前体mRNA剪接的调节。在人类癌症中看到的某些mRNA剪接缩写可能是由Wnt信号通路的激活诱导的。
Background & Aims: beta-Catenin is a downstream effector of the Writ signaling pathway and is believed to exert its oncogenic function by activating T-cell factor (TCF)/lymphoid enhancer factor (LEF) family transcriptional factors. However, it is still uncertain whether the diverse effects of beta-catenin are caused solely by aberrant gene transactivation. In this study, we used a proteomics approach to obtain further insight into the functional properties of nuclear beta-catenin. Methods: The protein assembly of a native beta-catenin-containing complex in nuclear extracts from a colorectal cancer cell line, DLD-1, was identified using immunoprecipitation and mass spectrometry. Results : beta-Catenin physically interacted with fusion (FUS)/translocated in liposarcoma (TLS) and various RNA-binding proteins. The expression of FUS/TLS was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells. The transient transfection of FUS suppressed beta-catenin-evoked gene transactivation of TCF/LEF, and beta-catenin transfection affected the splicing pattern of the E1A minigene and induced a novel splicing variant of estrogen receptor (ER)-beta exerting a dominant-negative activity. Conclusions: Human cancer expresses a large variety of alternatively spliced messenger RNA (mRNA), but the precise molecular mechanisms responsible for cancer-related alternative splicing are largely unknown. In this study, we demonstrated the interaction of beta-catenin with FUS/TLS and other RNA-binding proteins involved in the regulation of pre-mRNA splicing. Certain mRNA splicing abbreviations seen in human cancers may be induced-by the activation of the Wnt signaling pathway.