Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation

The telomerase reverse transcriptase component (TERT) is not expressed in m ost primary somatic human cells and tissues, but is upregulated in the majo rity of immortalized cell lines and tumors. Here, we identify the c-Myc tra nscription factor as a direct mediator of telomerase activation in primary human fibroblasts through its ability to specifically induce TERT gene expr ession. Through the use of a hormone inducible form of c-Myc (c-MSc-ER), we demonstrate that MSc-induced activation of the hTERT promoter requires an evolutionarily conserved E-box and that c-Myc-ER-induced accumulation of hT ERT mRNA takes place in the absence of de novo protein synthesis. These fin dings demonstrate that the TERT gene is a direct transcriptional target of c-Myc, Since telomerase activation frequently correlates with immortalizati on and telomerase functions to stabilize telomers in cycling cells, we test ed whether Myc-induced activation of TERT gene expression represents an imp ortant mechanism through which c-Myc acts to immortalize cells. Employing t he rat embryo fibroblast cooperation assay, we show that TERT is unable to substitute for c-Myc in the transformation of primary rodent fibroblasts, s uggesting that the transforming activities of Myc extend beyond its ability to activate TERT gene expression and hence telomerase activity.