This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ducrest, A.-L. Articles by Lingner, J. Search for Related Content PubMed PubMed Citation Articles by Ducrest, A.-L. Articles by Lingner, J.

Regulation of Human Telomerase Activity

Repression by Normal Chromosome 3 Abolishes Nuclear Telomerase Reverse Transcriptase Transcripts but Does Not Affect c-Myc Activity¹

Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland [A-L. D., M. A., Y. D. M., M. N., J. L.]; and Institute of Cancer Genetics and Pharmacogenomics, Department of Biological Sciences, Brunel University, Uxbridge UB8 3PH, United Kingdom [A. P. C., D. A. T., R. F. N.]

Telomerase is required for the complete replication of chromosomal ends. In tumors, the human telomerase reverse transcriptase subunit (hTERT) is up-regulated, thereby removing a critical barrier for unlimited cell proliferation. To understand more about hTERT regulation, we measured hTERT RNA levels by quantitative reverse transcription (RT)-PCR. Telomerase-positive cell lines were found to contain between 0.2 and 6 molecules of spliced hTERT RNA per cell, whereas in telomerase-negative cells, the number of molecules was below the sensitivity of the assay (<0.004 molecules/cell). Intron-containing, immature hTERT RNA was observed only in nuclei of telomerase-positive cells, which suggests that hTERT RNA levels are transcriptionally regulated. Microcell transfer of a normal chromosome 3 into the human breast carcinoma cell line (21NT) abolishes telomerase activity and induces senescence. Endogenous hTERT transcripts were undetectable in the nuclei of 21NT-chromosome 3 hybrids, even in cells permanently expressing a transfected hTERT cDNA. However, chromosome 3 transfer did not affect the expression of green fluorescent protein reporter constructs driven by up to 7.4 kb of noncoding DNA flanking the 5' end of the hTERT gene. Because direct up-regulation of hTERT through c-Myc overexpression had previously been reported, we investigated whether chromosome 3 transfer affected c-Myc activity. An at least 30-fold reduction of immature intron-containing hTERT RNA was observed after the introduction of a normal chromosome 3, but expression levels of c-Myc, Mad1, and other c-Myc target genes were unchanged. Our results suggest that telomerase is regulated primarily at the level of hTERT transcription by complex mechanisms involving regulatory elements distant from the 5' flanking region, and that the putative hTERT repressor on chromosome 3 does not regulate the expression of hTERT through c-Myc or one of its coregulators.

This article has been cited by other articles:

				M. Bellon and C. Nicot Regulation of Telomerase and Telomeres: Human Tumor Viruses Take Control J Natl Cancer Inst, January 16, 2008; 100(2): 98 - 108. [Abstract] [Full Text] [PDF]

				M. W. Freyer, R. Buscaglia, K. Kaplan, D. Cashman, L. H. Hurley, and E. A. Lewis Biophysical Studies of the c-MYC NHE III1 Promoter: Model Quadruplex Interactions with a Cationic Porphyrin Biophys. J., March 15, 2007; 92(6): 2007 - 2015. [Abstract] [Full Text] [PDF]

				S. Renaud, D. Loukinov, Z. Abdullaev, I. Guilleret, F. T. Bosman, V. Lobanenkov, and J. Benhattar Dual role of DNA methylation inside and outside of CTCF-binding regions in the transcriptional regulation of the telomerase hTERT gene Nucleic Acids Res., February 28, 2007; 35(4): 1245 - 1256. [Abstract] [Full Text] [PDF]

				S. Renaud, D. Loukinov, F. T. Bosman, V. Lobanenkov, and J. Benhattar CTCF binds the proximal exonic region of hTERT and inhibits its transcription Nucleic Acids Res., December 2, 2005; 33(21): 6850 - 6860. [Abstract] [Full Text] [PDF]

				J. M. Ritz, O. Kuhle, S. Riethdorf, B. Sipos, W. Deppert, C. Englert, and C. Gunes A Novel Transgenic Mouse Model Reveals Humanlike Regulation of an 8-kbp Human TERT Gene Promoter Fragment in Normal and Tumor Tissues Cancer Res., February 15, 2005; 65(4): 1187 - 1196. [Abstract] [Full Text] [PDF]

				S. Wang and J. Zhu The hTERT Gene Is Embedded in a Nuclease-resistant Chromatin Domain J. Biol. Chem., December 31, 2004; 279(53): 55401 - 55410. [Abstract] [Full Text] [PDF]

				B. S. Goueli and R. Janknecht Upregulation of the Catalytic Telomerase Subunit by the Transcription Factor ER81 and Oncogenic HER2/Neu, Ras, or Raf Mol. Cell. Biol., January 1, 2004; 24(1): 25 - 35. [Abstract] [Full Text] [PDF]

				K. Kraemer, S. Fuessel, U. Schmidt, M. Kotzsch, B. Schwenzer, M. P. Wirth, and A. Meye Antisense-mediated hTERT Inhibition Specifically Reduces the Growth of Human Bladder Cancer Cells Clin. Cancer Res., September 1, 2003; 9(10): 3794 - 3800. [Abstract] [Full Text] [PDF]

				I. Horikawa and J. C. Barrett Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms Carcinogenesis, July 1, 2003; 24(7): 1167 - 1176. [Abstract] [Full Text] [PDF]

				K.-D. Wu, L. M. Orme, J. Shaughnessy Jr, J. Jacobson, B. Barlogie, and M. A. S. Moore Telomerase and telomere length in multiple myeloma: correlations with disease heterogeneity, cytogenetic status, and overall survival Blood, June 15, 2003; 101(12): 4982 - 4989. [Abstract] [Full Text] [PDF]

				S. Wang and J. Zhu Evidence for a Relief of Repression Mechanism for Activation of the Human Telomerase Reverse Transcriptase Promoter J. Biol. Chem., May 23, 2003; 278(21): 18842 - 18850. [Abstract] [Full Text] [PDF]

				H. Szutorisz, J. Lingner, A. P. Cuthbert, D. A. Trott, R. F. Newbold, and M. Nabholz A Chromosome 3-encoded Repressor of the Human Telomerase Reverse Transcriptase (hTERT) Gene Controls the State of hTERT Chromatin Cancer Res., February 1, 2003; 63(3): 689 - 695. [Abstract] [Full Text] [PDF]

				R. F. Newbold The significance of telomerase activation and cellular immortalization in human cancer Mutagenesis, November 1, 2002; 17(6): 539 - 550. [Abstract] [Full Text] [PDF]

				I. Horikawa, P. L. Cable, S. J. Mazur, E. Appella, C. A. Afshari, and J. C. Barrett Downstream E-Box-mediated Regulation of the Human Telomerase Reverse Transcriptase (hTERT) Gene Transcription: Evidence for an Endogenous Mechanism of Transcriptional Repression Mol. Biol. Cell, August 1, 2002; 13(8): 2585 - 2597. [Abstract] [Full Text] [PDF]

				J.-L. Mergny, J.-F. Riou, P. Mailliet, M.-P. Teulade-Fichou, and E. Gilson Natural and pharmacological regulation of telomerase Nucleic Acids Res., February 15, 2002; 30(4): 839 - 865. [Abstract] [Full Text] [PDF]