Transactivation of the proenkephalin gene promoter by the Tax1 protein of human T-cell lymphotropic virus type I.

Human T-cell lymphotropic virus type I (HTLV-I), an etiologic agent for adult T-cell leukemia, is strongly associated with certain neurological diseases. The HTLV-I genome encodes a protein, Tax1, that transactivates viral gene transcription. CD4-positive T helper lymphocytes express the proenkephalin gene, and enkephalins have been implicated as neuroimmunomodulators. We have investigated the effect of Tax1 on the proenkephalin gene promoter in C6 rat glioma cells and demonstrated its transactivation. Analysis using 5' deletion mutants of the promoter region showed that sequences upstream of base pair -190 are necessary for maximal transactivation. Forskolin, a cAMP modulator, synergistically increased Tax1-mediated transactivation of the proenkephalin promoter. Neither Tax1 transactivation alone nor Tax1/cAMP synergism exclusively involved cAMP-responsive elements. Endogenous proenkephalin gene expression increased in Tax1-expressing C6 cells. Since HTLV-I infects lymphocytes, which express proenkephalin mRNA, Tax1 transregulation of proenkephalin expression may provide bidirectional communication between the nervous and immune systems in HTLV-I-related diseases. IMAGES:

人类T细胞嗜淋巴病毒I型（Human T-cell lymphotropic virus type I, HTLV-I）是成人T细胞白血病的致病病原体，与多种神经系统疾病存在显著关联。HTLV-I基因组编码Tax1蛋白，该蛋白可反式激活病毒基因的转录过程。CD4阳性辅助T淋巴细胞（CD4-positive T helper lymphocytes）表达前脑啡肽基因（proenkephalin gene），而脑啡肽（enkephalins）已被证实为一类重要的神经免疫调节剂。本研究在C6大鼠胶质瘤细胞（C6 rat glioma cells）中探究了Tax1对前脑啡肽基因启动子的调控作用，并证实其具备反式激活活性。通过对启动子区域的5'端缺失突变体（5' deletion mutants）开展分析，结果显示，碱基对-190上游的序列是实现最大反式激活活性所必需的核心区段。毛喉素（Forskolin）作为一种环腺苷酸（cAMP）调节剂，可协同增强Tax1介导的前脑啡肽基因启动子反式激活活性。单独的Tax1反式激活作用，或是Tax1与cAMP的协同效应，均并非仅依赖于环腺苷酸应答元件（cAMP-responsive elements）。在表达Tax1的C6细胞中，内源性前脑啡肽基因的表达水平显著上调。鉴于HTLV-I可感染表达前脑啡肽mRNA的淋巴细胞，Tax1对前脑啡肽表达的反式调控或许为HTLV-I相关疾病中神经系统与免疫系统之间的双向通讯提供了潜在的分子基础。IMAGES: