The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity
The tumor suppressor Fhit acts as a repressor of β-catenin transcriptional activity
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DOI：
10.1073/pnas.0703664105
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发表时间：
2007-12-18
影响因子：
11.1
通讯作者：
Huber, Otmar
中科院分区：
文献类型：
--
作者：
Weiske, Jorg;Albring, Kai Frederik;Huber, Otmar
靶向脆性组氨酸三联体（Fhit）基因的染色体3p14.2上的Fra 3B基因座代表人类基因组中最常见的脆性位点之一，并且与多种人类肿瘤中的早期癌前和恶性疾病相关。Fhit被归类为肿瘤抑制因子，然而，其功能的分子机制尚未完全确定。在这里，我们报告说，Fhit协会与淋巴增强子结合因子1/T细胞因子/β-连环蛋白复合物直接结合到β-连环蛋白，一个主要的球员在经典的Writ途径，在许多形式的人类癌症的失调。Fhit与β-连环蛋白C-末端结构域结合，抑制靶基因如细胞周期蛋白D1、轴蛋白2、MMP-14和生存素的转录。敲低Fhit逆转了这种效应，而当β-连环蛋白同时被敲低时，这种逆转是检测不到的。作为二腺苷-多磷酸水解酶的Fhit酶活性对于β-连环蛋白介导的转录的下调不是必需的，如用酶失活的Fhit-H96 N蛋白所检查的。ChIP揭示了Fhit/β-连环蛋白复合物向靶基因启动子的募集。在软琼脂测定中，Fhit和β-连环蛋白参与调节锚定非依赖性生长。这些观察结果分配给肿瘤抑制因子Fhit在β-连环蛋白介导的基因转录的调节中的意想不到的作用。
The Fra3B locus on chromosome 3p14.2 targeting the fragile histidine triad (Fhit) gene represents one of the most common fragile sites of the human genome and is associated with early preneoplastic and malignant disorders in multiple human tumors. Fhit was classified as a tumor suppressor; however, the molecular mechanisms of its function are not well established. Here, we report that Fhit associates with the lymphoid enhancer-binding factor 1/T cell factor/beta-catenin complex by directly binding to P-catenin, a major player in the canonical Writ pathway that is deregulated in numerous forms of human cancer. In binding to the P-catenin C-terminal domain, Fhit represses transcription of target genes such as cyclin D1, axin2, MMP-14, and survivin. Knockdown of Fhit reversed this effect, whereas this reversal was not detectable when beta-catenin was knocked down simultaneously. The Fhit enzymatic activity as a diadenosine-polyphosphate hydrolase is not required for the down-regulation of beta-catenin-mediated transcription as examined with an enzymatic inactive Fhit-H96N protein. ChlPs revealed recruitment of Fhit/beta-catenin complexes to target gene promoters. In soft agar assays Fhit and beta-catenin are involved in regulation of anchorage-independent growth. These observations assign to the tumor suppressor Fhit an unexpected role in the regulation of beta-catenin-mediated gene transcription.