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

focusyltransferase VII （fuf - t VII）基因编码一种白细胞/内皮细胞粘附分子配体sialyl Lewis X合成酶，其表达在某些癌细胞的炎症甚至转移中起重要作用。我们发现成人t细胞白血病患者的白血病细胞强烈表达sialyl Lewis X，其表达水平与白血病细胞的血管外浸润程度显著相关，并且f - t VII基因被HTLV-1 Tax反激活。我们在Fuc-T VII基因的启动子中发现了税收响应元件（TaxRE），该元件包含一个半回文camp响应元件（CRE）。我们发现CREB/ATF家族的几个成员和未确定的因子与HTLV-1长末端重复启动子中的税收响应病毒CRE非常相似。除了结构上的相似性，报告者分析显示TaxRE在功能上也与病毒CRE相似，不同于细胞CRE，如生长抑素基因启动子**。为了阐明这种转激活在TaxRE中的机制，我们利用酵母单杂交系统克隆了编码参与这种转激活的TaxRE结合因子的cdna。除了CREB/ATF家族成员外，一个cDNA被鉴定为转录因子T box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分化中起关键作用。然而，T-bet的确切结合序列和交互激活机制仍有待研究。我们发现T-bet实际上与TaxRE的5'部分结合，并且在体内也与Tax相关，并且T-bet参与了与CREB/ATF家族和Tax相关的fuct - VII基因的调控。这些结果提示T-bet在HTLV-1税介导的f - t VII基因转激活中起重要作用。

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.