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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References
Henriksson, M. & Luscher, B. Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv. Cancer. Res. 68, 109–182 ( 1996).
Bouchard, C., Staller, P. & Eilers. M. Control of cell proliferation by Myc. Trends Cell Biol. 8, 202–206 (1998).
Grandori, C. & Eisenman, R.N. Myc target genes. Trends Biochem. Sci. 22, 177–181 (1997).
Nugent, C.I. & Lundblad, V. The telomerase reverse transcriptase: components and regulation. Genes Dev. 12, 1073–1085 (1998).
Wright, W.E. & Shay, J.W. Time, telomere, and tumour: is cellular senescence more than an anticancer mechanism? Trends Cell Biol. 5, 293–297 ( 1995).
Lingner, J. & Cech, T. Telomerase and chromosome end maintenance. Curr. Opin. Genet. Dev. 8, 226– 232 (1998).
Lingner, J. et al. Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276, 561–567 (1997).
Nakamura, T.M. et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 277, 955– 959 (1997).
Meyerson, M. et al. hEST2, the putative human telomerase catalytic subunit gene, is up–regulated in tumour cells and during immortalization. Cell 90, 785–795 ( 1997).
Bodnar, A.G. et al. Extension of life–span by introduction of telomerase into normal human cells. Science 279, 350 –352 (1998).
Counter, C.M. et al. Telomerase activity is restored in human cells by ectopic expression of hTERT(hEST2), the catalytic subunit of telomerase. Oncogene 16, 1217–1222 ( 1998).
Ramakrishnan, S., Eppenberger, U., Mueller, H., Shinkai, Y. & Narayanan, R. Expression profile of the putative catalytic subunit of the telomerase gene. Cancer Res. 58, 622–625 (1998).
Greenberg, R.A., Allsopp, R.C., Chin, L., Morin, G.B. & DePinho, R.A. Expression of mouse telomerase reverse transcriptase during development, differentiation, and proliferation. Oncogene 16, 1723–1730 ( 1998).
Wang, J., Xie, L.Y., Allan, S., Beach, D. & Hannon, G.J. Myc activates telomerase. Genes Dev. 12, 1769–1774 (1998).
Gu, W., Cechova, K., Tassi, V. & Dalla–Favera, R. Opposite regulation of gene transcription and cell proliferation by c–Myc and Max. Proc. Natl Acad. Sci. USA 90, 2935– 2939 (1993).
Larsson, L.–G. et al. Phorbol ester–induced terminal differentiation is inhibited in human U–937 monoblastic cells expressing a v–Myc oncogene. Proc. Natl Acad. Sci. USA 85, 2638– 2642 (1988).
Kempkes, B. et al. B–cell proliferation and induction of early G1–regulating proteins by Epstein–Barr virus mutants conditional for EBNA2. EMBO J. 14, 88–96 ( 1995).
Holt, S.E., Wright, W.E. & Shay, J.W. Regulation of telomerase activity in immortal cell lines. Mol. Cell. Biol. 16, 2932– 2939 (1996).
Igarashi, H. & Sakaguchi, N. Telomerase activity is induced in human peripheral B lymphocytes by the stimulation to antigen receptor. Blood 89, 1299–1307 (1997).
Littlewood, T.D., Hancock, D.C., Danielian, P.C., Parker, M.G. & Evan, G.I. A modified estrogen receptor ligand–binding domain as an improved switch for the regulation of heterologous proteins. Nucleic Acids Res. 23, 1686– 1690 (1995).
Sasson, S. Equilibrium binding analysis of estrogen agonists and antagonists: relation to the activation of the estrogen receptor. Pathol. Biol. 39, 59–69 (1991).
Grandori, C., Mac, J., Siebelt, F., Ayer, D.E. & Eisenman, R.N. Myc–Max heterodimers activate a DEAD box gene and interact with multiple E box–related sites in vivo. EMBO J. 15, 4344–4357 ( 1996).
Ayer, D.E., Kretzner, L. & Eisenman, R.N. Mad: a heterodimeric partner for Max that antagonizes Myc transcriptional activity. Cell 72, 211 –222 (1993).
Nordeen, S.K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques 6, 454–458 (1988).
Kim, N.M. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011– 2015 (1994).
Pan, C., Xue, B.H., Ellis, T.M., Peace, D.J. & Diaz, M.O. Changes in telomerase activity and telomere length during human T lymphocyte senescence. Exp. Cell Res. 231, 346–353 (1997).
Polack, A. et al. c–Myc activation renders proliferation of Epstein–Barr virus(EBV)–transformed cells independent of EBV nuclear antigen 2 and latent membrane protein 1. Proc. Natl Acad. Sci. USA 93, 10411–10416 (1996).
Dalla–Favera, R. et al. Cloning and characterization of different human sequences related to the onc gene (v–myc) of avian myelocytomatosis virus (MC29). Proc. Natl Acad. Sci. USA 79, 6497– 6501 (1982).
Wu, K.J., Polack, A. & Dalla–Favera, R. Coordinated regulation of iron controlling genes, H–ferritin and IRP2, by c–MYC. Science (in press).
Stone, J. et al. Definition of regions in human c–myc that are involved in transformation and nuclear localization. Mol. Cell. Biol. 7, 1697–1709 (1987).
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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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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DOI: https://doi.org/10.1038/6010