Poly(ADP-ribose) polymerase-1 is a component of the oncogenic T-cell factor-4/β-catenin complex
Poly(ADP-ribose) polymerase-1 is a component of the oncogenic T-cell factor-4/β-catenin complex
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DOI：
10.1053/j.gastro.2005.03.007
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发表时间：
2005-06-01
期刊：
影响因子：
29.4
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Idogawa, M;Yamada, T;Hirohashi, S
背景与目的：T细胞因子-4（TCF-4）调控肠上皮细胞生长和分化相关基因。这些TCF-4调节基因的β-catenin蛋白的异常反式激活在早期肠癌发生中起着至关重要的作用，并且TCF-4/β-catenin复合物的转录机制可能包含分子治疗的靶点。我们通过蛋白质组学的方法探索了TCF-4/β-连环蛋白转录复合物的分子组成。方法和结果：大约112千道尔顿的蛋白质与在HEK 293细胞中瞬时表达的FLAG标记的TCF-4一致地共免疫沉淀，并且该蛋白质通过质谱鉴定为聚（ADP-核糖）聚合酶-1（PARP-1）。PARP-1与TCF-4物理相互作用，并增强β-连环蛋白/TCF-4复合物的转录活性。通过RNA干扰敲低PARP-1显著抑制结直肠癌细胞的转录活性和增殖。DNA损伤诱导的PARP-1蛋白的自身聚ADP核糖基化抑制了PARP-1与TCF-4的功能性相互作用。PARP-1在家族性腺瘤性息肉病患者和多发性肠息肉病小鼠的肠腺瘤中过表达。PARP-1的表达与β-连环蛋白的积累和肠上皮细胞的未分化状态密切相关。结论：在这项研究中，我们确定PARP-1作为一种新的β-连环蛋白/TCF-4复合物的共激活剂。尽管PARP-1被认为对癌发生起保护作用，但PARP-1的这些表达模式和功能特性高度提示其参与早期结直肠癌发生。
Background & Aims: T-cell factor (TCF)-4 regulates a certain set of genes related to growth and differentiation of intestinal epithelial cells. Aberrant transactivation of these TCF-4-regulated genes by beta-catenin protein plays a crucial role in early intestinal carcinogenesis, and the transcriptional machinery of the TCF-4/beta-catenin complex is likely to contain targets for molecular therapy. We explored the molecular composition of the TCF-4/beta-catenin transcriptional complex by means of proteomics. Methods & Results: A protein of approximately 112 kilodaltons was consistently coimmunoprecipitated with FLAG-tagged TCF-4 transiently expressed in HEK293 cells, and the protein was identified by mass spectrometry as poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 physically interacted with TCF-4 and augmented the transcriptional activity of the beta-catenin/TCF-4 complex. Knockdown of PARP-1 by RNA interference significantly suppressed both transcriptional activity and proliferation by colorectal cancer cells. Auto-polyADP-ribosylation of the PARP-1 protein induced by DNA damage inhibited the functional interaction of PARP-1 with TCF-4. PARP-1 was overexpressed in the intestinal adenomas of patients with familial adenomatous polyposis and multiple intestinal polyposis mice. The expression of PARP-1 was closely associated with the accumulation of beta-catenin and with the undifferentiated status of intestinal epithelial cells. Conclusions: In this study, we identified PARP-1 as a novel coactivator of the beta-catenin/TCF-4 complex. Although PARP-1 has been believed to play a protective role against carcinogenesis, these expression patterns and functional properties of PARP-1 were highly suggestive of its participation in early colorectal carcinogenesis.