Cheng Wing-Shing, Giandomenico Valeria, Pastan Ira, Essand Magnus
Clinical Immunology, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden.
Endocrinology. 2003 Aug;144(8):3433-40. doi: 10.1210/en.2003-0121.
TARP (T cell receptor gamma-chain alternate reading frame protein) is uniquely expressed in males in prostate epithelial cells and prostate cancer cells. Here we demonstrate that TARP expression is regulated by testosterone at the transcriptional level through specific binding of androgen receptor to an androgen response element in the proximal TARP promoter. We further demonstrate that the promoter specifically initiates reporter gene expression in TARP-positive prostate cancer cell lines. To develop a regulatory sequence for prostate-specific gene expression, we constructed a chimeric sequence consisting of the TARP promoter and the prostate-specific antigen (PSA) enhancer. We found that in the prostatic adenocarcinoma cell line LNCaP, the transcriptional activity of the regulatory sequence consisting of a TARP promoter and PSA enhancer is 20 times higher than the activity of a regulatory sequence consisting of the PSA promoter and PSA enhancer. Thus, our studies define a regulatory sequence that may be used to restrict expression of therapeutic genes to prostate cancer cells and may therefore play a role in prostate cancer gene therapy.
TARP（T细胞受体γ链交替阅读框蛋白）在前列腺上皮细胞和前列腺癌细胞中仅在男性中特异性表达。在此我们证明，雄激素受体通过与TARP近端启动子中的雄激素反应元件特异性结合，在转录水平上调控TARP的表达。我们进一步证明，该启动子在TARP阳性前列腺癌细胞系中特异性启动报告基因的表达。为了开发一种用于前列腺特异性基因表达的调控序列，我们构建了一个由TARP启动子和前列腺特异性抗原（PSA）增强子组成的嵌合序列。我们发现，在前列腺腺癌细胞系LNCaP中，由TARP启动子和PSA增强子组成的调控序列的转录活性比由PSA启动子和PSA增强子组成的调控序列的活性高20倍。因此，我们的研究确定了一种调控序列，该序列可用于将治疗性基因的表达限制在前列腺癌细胞中，因此可能在前列腺癌基因治疗中发挥作用。
