Identification of SP5 as a downstream gene of the beta-catenin/Tcf pathway and its enhanced expression in human colon cancer.
Identification of SP5 as a downstream gene of the beta-catenin/Tcf pathway and its enhanced expression in human colon cancer.
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DOI：
10.3892/ijo.27.6.1483
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发表时间：
2005-12
影响因子：
5.2
通讯作者：
Meiko Takahashi;Y. Nakamura;K. Obama;Y. Furukawa
中科院分区：
文献类型：
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作者：
Meiko Takahashi;Y. Nakamura;K. Obama;Y. Furukawa
APC、CTNNB1、AXIN1或AXIN2的突变导致β -连环蛋白降解途径受损，并导致β -连环蛋白在多种人类癌症中积累。积累的β -连环蛋白随后与Tcf/LEF转录因子结合并激活其靶基因。为了详细揭示积累的β -catenin在结直肠癌发生中的作用，我们通过cDNA芯片寻找β -catenin/Tcf信号通路相关基因。我们鉴定并鉴定了一种人类基因SP5，该基因通过野生型APC转导到SW480细胞中，在β -catenin缺失后下调。SP5是Sp转录因子家族的一员，与许多基因启动子中的GC盒或密切相关的序列结合，控制其表达。报告基因分析和电迁移分析显示，该基因5'侧区-285和-279之间的DNA片段是β -catenin/Tcf4复合物的靶标。我们的研究结果表明，SP5是Wnt信号通路中一个新的直接下游靶点。
Mutations in APC, CTNNB1, AXIN1 or AXIN2 cause impairment in the beta-catenin degradation pathway and result in accumulation of beta-catenin in a wide range of human cancers. Accumulated beta-catenin then associates with Tcf/LEF transcription factors and transactivates their target genes. To uncover in detail the role of accumulated beta-catenin in colorectal carcinogenesis, we searched for genes involved in the beta-catenin/Tcf signaling pathway by cDNA microarray. We identified and characterized a human gene, SP5, that was down-regulated after depletion of beta-catenin by transduction of wild-type APC into SW480 cells. SP5 is a member of the Sp transcription factor family, which binds to the GC box or closely related sequences in promoters of many genes and control their expression. Reporter assays and an electromobility-shift assay revealed a DNA fragment between -285 and -279 in the 5' flanking region of this gene to be a target of the beta-catenin/Tcf4 complex. Our results indicate that SP5 is a novel direct down-stream target in the Wnt signaling pathway.