Abstract
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.
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Acknowledgements
We would like to thank Arthur Skoultchi for providing MEL and Myc56MEL cells, Scott Lowe for the mouse ecotropic receptor and the pBABE-RASG12V plasmids, Nicole Schreiber-Agus for critical review of the manuscript, Tin Hoang and Michael Lombardi for technical support, and Joel Bolonick for bioinformatics assistance. RAG is supported by NIH Training Grant 5T32GM07491. RAD is supported by grants (R01HD28317, R01EY09300, R01EY11267) from the National Institutes of Health, an AHA Grant-in-AID. RAD is a recipient of the Irma T Hirschl Award and an American Cancer Society Research Professor.
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Greenberg, R., O'Hagan, R., Deng, H. et al. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene 18, 1219–1226 (1999). https://doi.org/10.1038/sj.onc.1202669
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DOI: https://doi.org/10.1038/sj.onc.1202669
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