Joshi J B, Dave H P
Laboratory of Biochemical Genetics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1992 Feb 1;89(3):1006-10. doi: 10.1073/pnas.89.3.1006.
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.
人类嗜T细胞病毒I型（HTLV-I）是成人T细胞白血病的病原体，与某些神经系统疾病密切相关。HTLV-I基因组编码一种蛋白Tax1，它能反式激活病毒基因转录。CD4阳性T辅助淋巴细胞表达前脑啡肽原基因，脑啡肽被认为是神经免疫调节剂。我们研究了Tax1对C6大鼠胶质瘤细胞中前脑啡肽原基因启动子的影响，并证实了其反式激活作用。对启动子区域5'缺失突变体的分析表明，-190碱基对上游的序列对于最大程度的反式激活是必需的。环磷腺苷调节剂福斯高林协同增强了Tax1介导的前脑啡肽启动子的反式激活。单独的Tax1反式激活或Tax1/环磷腺苷协同作用均不完全涉及环磷腺苷反应元件。在表达Tax1的C6细胞中，内源性前脑啡肽原基因表达增加。由于HTLV-I感染表达前脑啡肽原mRNA的淋巴细胞，Tax1对前脑啡肽表达的反式调节可能在HTLV-I相关疾病中提供神经和免疫系统之间的双向通讯。
