Transcriptional Regulation of Selectin-ligand Synthetase (Fucosyltransferase VII) Related to Ability of Metastasis in Cancer Cells

选择素配体合成酶（岩藻糖基转移酶 VII）的转录调控与癌细胞转移能力相关

基本信息

批准号：
13670582
负责人：
HIRAIWA Nozomu
金额：
$ 2.24万
依托单位：
Aichi Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670582/
关键词：
Selectin-ligand fucosyltransferase VII Tax CRE T-box one-hybrid CREB ATF T-bet fucosyltransferrase VII One-hybrid法 F7CAF-1

项目摘要

Fucosyltransferase VII (Fuc-T VII) gene encodes a leukocyte/endothelial cell adhesion molecule -ligand sialyl Lewis X synthetase, the expression of which plays important roles in inflammation and even in metastasis of some cancer cells. We have shown that leukemia cells in patients with adult T-cell leukemia strongly express the sialyl Lewis X, the expression level of which significantly correlates with the degree of extravascular infiltration of the leukemic cells, and that the Fuc-T VII gene is transactivated by the HTLV-1 Tax.We identified the Tax-responsive element (TaxRE) in the promoter of the Fuc-T VII gene, which contains a half-palindromic cAMP-responsive element (CRE). We found that several members of the CREB/ATF family and unidentified factors bind to this TaxRE being much homologous to the Tax-responsive viral CRE in the HTLV-1 long terminal repeat-promoter. In addition to the structural similarity, reporter analysis revealed that the TaxRE also bears functional resemblance to the viral CRE, differing from cellular CREs such as ** the somatostatin gene promoter.To clarify the mechanism of such fransactivation in the TaxRE, we utilized the yeast one-hybrid system to clone cDNAs encoding TaxRE-binding factors involved in this transactivation. Besides members of CREB/ATF family, one cDNA was identified as the human homologue of one of the transcription factor T box family, T-bet, T-bet reportedly plays a critical role in differentiation of T lymphocyte to Th1. However, the exact binding sequence of T-bet and the mechanism of transactivation remain to be studied. We showed that T-bet actually binds to the 5' part of the TaxRE and also associates with Tax in vivo, and that T-bet is involved in the regulation of the Fuc-T VII gene in association with CREB/ATF family and Tax. These results suggest an important role for T-bet in HTLV-1 Tax-mediated Fuc-T VII gene transactivation.

岩藻糖基转移酶VII（Fuc-T VII）基因编码白细胞/内皮细胞粘附分子-配体唾液酸Lewis X合成酶，其表达在炎症甚至某些癌细胞的转移中发挥重要作用。我们发现，成人T细胞白血病患者的白血病细胞强烈表达唾液酸化Lewis X，其表达水平与白血病细胞血管外浸润程度显着相关，并且Fuc-T VII基因被反式激活HTLV-1 Tax。我们在Fuc-T VII基因的启动子中鉴定出了Tax反应元件（TaxRE），该元件含有一个半回文结构cAMP 响应元件 (CRE)。我们发现 CREB/ATF 家族的几个成员和未识别的因子与该 TaxRE 结合，与 HTLV-1 长末端重复启动子中的 Tax 反应性病毒 CRE 非常同源。除了结构相似性之外，记者分析还发现，TaxRE 还与病毒 CRE 具有功能相似性，但与细胞 CRE（例如生长抑素基因启动子）不同。为了阐明 TaxRE 中这种反式激活的机制，我们利用了酵母单杂交系统克隆编码参与该反式激活的TaxRE结合因子的cDNA。除了CREB/ATF家族的成员外，一种cDNA被鉴定为转录因子T盒家族之一T-bet的人类同源物，据报道T-bet在T淋巴细胞向Th1的分化中发挥着关键作用。然而，T-bet的确切结合序列和反式激活机制仍有待研究。我们表明，T-bet 实际上与 TaxRE 的 5' 部分结合，并且还与体内的 Tax 相关，并且 T-bet 参与与 CREB/ATF 家族和 Tax 相关的 Fuc-T VII 基因的调节。这些结果表明 T-bet 在 HTLV-1 Tax 介导的 Fuc-T VII 基因反式激活中发挥重要作用。