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Direct activation of TERT transcription by c-MYC

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.

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Figure 1: MYC overexpression is associated with induction of TERT expression and increased telomerase activity.
Figure 2: Induction of TERT expression and telomerase activity by c–MYC in the absence of cell proliferation.
Figure 3: Upregulation of TERT expression by c–MYC is independent of new protein synthesis.
Figure 4: C–MYC/MAX binding sites in the promoter region of human TERT .
Figure 5: Transcriptional activation of the TERT promoter by c–MYC.

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Acknowledgements

We thank T. Littlewood for pBabe–MycER vectors; B. Kempkes and G. Bornkamm for the EREB cell line; Y. Shiio for baculovirus MAX; O. Zilian for the human genomic library; Geron for the TERT cDNA clone; M. Nabholz, A.L. Ducrest, B. Amati and O. Zilian for useful discussions; R. Eisenman for support and critical discussions; and S. Hirst for technical assistance. J.L.'s laboratory is supported by grants from the Swiss National Science Foundation, Swiss Cancer Research and the ISREC. J.L. is recipient of a START–fellowship from the Swiss National Science Foundation. K.J.W. is a Fellow of the Leukemia Society of America. This work was supported in part by NIH grant CA37165, CA75125–01 and CA20525.

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Correspondence to Riccardo Dalla-Favera.

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Wu, KJ., Grandori, C., Amacker, M. et al. Direct activation of TERT transcription by c-MYC. Nat Genet 21, 220–224 (1999). https://doi.org/10.1038/6010

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