Direct activation of TERT transcription by c-MYC

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Abstract
The MYC proto-oncogene encodes a ubiquitous transcription factor (c–MYC) involved in the control of cell proliferation and differentiation1. Deregulated expression of c–MYC caused by gene amplification, retroviral insertion, or chromosomal translocation is associated with tumorigenesis2. The function of c–MYC and its role in tumorigenesis are poorly understood because few c–MYC targets have been identified3. Here we show that c–MYC has a direct role in induction of the activity of telomerase, the ribonucleoprotein complex expressed in proliferating and transformed cells, in which it preserves chromosome integrity by maintaining telomere length4,5,6. c–MYC activates telomerase by inducing expression of its catalytic subunit, telomerase reverse transcriptase7,8,9 (TERT). Telomerase complex activity is dependent on TERT, a specialized type of reverse transcriptase10,11. TERT and c–MYC are expressed in normal and transformed proliferating cells, downregulated in quiescent and terminally differentiated cells1,9,12,13, and can both induce immortalization when constitutively expressed in transfected cells2,10,11. Consistent with the recently reported association between MYC overexpression and induction of telomerase activity14, we find here that the TERT promoter contains numerous c–MYC–binding sites that mediate TERT transcriptional activation. c–MYC–induced TERT expression is rapid and independent of cell proliferation and additional protein synthesis, consistent with direct transcriptional activation of TERT. Our results indicate that TERT is a target of c–MYC activity and identify a pathway linking cell proliferation and chromosome integrity in normal and neoplastic cells.