【摘要】 端粒酶由端粒结合蛋白(telomeraseassociatedproteinI,TPI)、人类端粒酶RNA(humantelom eraseRNAtranscript,hTR)和端粒酶催化蛋白亚单位(humantelomerasereversetranscriptase,hTERT)3个主要成分构成。端粒酶在肿瘤发生、发展过程中起着重要作用,是迄今为止最为广谱的肿瘤分子标志物,已成为肿瘤基因治疗的新靶点。TPI在调节端粒长度、维持端粒的完整方面发挥重要作用,TRF(telomericrepeatbindingfactor)的改变可直接引发凋亡信号,通过hTR模板区突变、设计模板区RNA及其周围序列互补的反义寡核苷酸(ASODN)以封闭hTR模板区,或根据hTR成分设计合成核酶来切割hTR靶序列均可抑制肿瘤细胞端粒酶活性并诱导其凋亡。而hTERT是端粒酶活性的主要调控亚单位,利用hTERT启动子的癌细胞相对特异的转录活性,可将其作为肿瘤的基因治疗靶标;另外,模拟端粒序列设计合成端粒酶底物,竞争性抑制端粒DNA反转录过程及通过微细胞融合和染色体转移技术亦可抑制端粒酶活性,阻止端粒延长。在今后研究中,如果能进一步明确端粒酶作用的分子机制、建立合适的动物模型、排除端粒酶抑制剂的可能存在的毒性作用、提高其作用的组织特异性,以端粒酶为靶点的肿瘤基因治疗将具有广阔的应用前景。更多还原

【Abstract】 Telomerases are composed of telomerase associated protein (TPI), human telomerase RNA component (hTER) and human telomerase reverse transcriptase (hTERT). Telomerase plays a critical role in the progression or maintenance of malignant tumor. Telomerases that are the broad molecule notation of tumor become an exceptional target for tumor gene therapy. TPI plays the important role of regula ting length and maintaining integrity of telomerase. The changing of TRF can guide to apoptosis. Evoking mutation of hTR templat, designing antisense oligonucleotide of hTR templat to block it, or synthesizing ribozyme to cut hTR’s RNA can reduce telomerase activity and induce apoptosis. hTERT acts as a mainly regulating subunit gene of human telomerase enzymatic activity. hTERT promoter, which is relatively distinct in transcriptive activity, can be the target of tumor gene therapy. Besides, designing and synthesi zing telomerase substrate that can competitively inhibit telomeric RNA’s reverse transcriptive course. Some others found that cell fusion and chromosome transference also can reduce telomerase activity and shorten the telomere length. Henceforth, if we can solve such questions as further clearing telomerase acting mechanism, building appropriate animal model, getting rid of telomerase inhibitors’ potential toxicity, and enhancing telomerase inhibitors’ cell acting distinction, tumor gene therapy of telomerase target will have a bright future.更多还原