Greenberg R A, O'Hagan R C, Deng H, Xiao Q, Hann S R, Adams R R, Lichtsteiner S, Chin L, Morin G B, DePinho R A
Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Oncogene. 1999 Feb 4;18(5):1219-26. doi: 10.1038/sj.onc.1202669.
The telomerase reverse transcriptase component (TERT) is not expressed in most primary somatic human cells and tissues, but is upregulated in the majority of immortalized cell lines and tumors. Here, we identify the c-Myc transcription factor as a direct mediator of telomerase activation in primary human fibroblasts through its ability to specifically induce TERT gene expression. Through the use of a hormone inducible form of c-Myc (c-Myc-ER), we demonstrate that Myc-induced activation of the hTERT promoter requires an evolutionarily conserved E-box and that c-Myc-ER-induced accumulation of hTERT mRNA takes place in the absence of de novo protein synthesis. These findings demonstrate that the TERT gene is a direct transcriptional target of c-Myc. Since telomerase activation frequently correlates with immortalization and telomerase functions to stabilize telomers in cycling cells, we tested whether Myc-induced activation of TERT gene expression represents an important mechanism through which c-Myc acts to immortalize cells. Employing the rat embryo fibroblast cooperation assay, we show that TERT is unable to substitute for c-Myc in the transformation of primary rodent fibroblasts, suggesting that the transforming activities of Myc extend beyond its ability to activate TERT gene expression and hence telomerase activity.
端粒酶逆转录酶组分（TERT）在大多数原代人体细胞和组织中不表达，但在大多数永生化细胞系和肿瘤中上调。在此，我们鉴定出c-Myc转录因子是原代人成纤维细胞中端粒酶激活的直接介导因子，其通过特异性诱导TERT基因表达的能力来实现。通过使用激素诱导形式的c-Myc（c-Myc-ER），我们证明Myc诱导的hTERT启动子激活需要一个进化上保守的E盒，并且c-Myc-ER诱导的hTERT mRNA积累在没有从头蛋白质合成的情况下发生。这些发现表明TERT基因是c-Myc的直接转录靶标。由于端粒酶激活通常与永生化相关，并且端粒酶在循环细胞中起到稳定端粒的作用，我们测试了Myc诱导的TERT基因表达激活是否代表c-Myc使细胞永生化的重要机制。利用大鼠胚胎成纤维细胞合作试验，我们表明TERT在原代啮齿动物成纤维细胞转化中不能替代c-Myc，这表明Myc的转化活性超出了其激活TERT基因表达从而激活端粒酶活性的能力。
