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A more recent version of this article appeared on August 1, 2002
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Submitted on November 8, 2001
Revised on April 1, 2002
Accepted on May 1, 2002
1 Laboratory of Biosystems and Cancer, Cancer and Aging Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709
3 Laboratory of Cell Biology, Chemical Immunology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
* Corresponding author. E-mail address: horikawi{at}mail.nih.gov.
Regulation of the hTERT gene encoding the telomerase catalytic subunit plays an important role in human cell senescence, immortalization and carcinogenesis. By examining the activity of various deleted or mutated hTERT promoter fragments, we show that an E-box element downstream of the transcription initiation site is critical to differential hTERT transcription between the telomerase/hTERT-positive renal cell carcinoma cell line (RCC23) and its telomerase/hTERT-negative counterpart containing a transferred, normal chromosome 3 (RCC23+3). This E-box element mediated repression of hTERT transcription in RCC23+3 but not in RCC23. A copy number-dependent enhancement of the repression suggested active repression, rather than loss of activation, in RCC23+3. Endogenous expression levels of c-Myc or Mad1, which could activate or repress hTERT transcription when overexpressed, did not account for the differential hTERT transcription. Gel mobility shift assays identified the upstream stimulatory factors (USF) as a major E-box-binding protein complex in both RCC23 and RCC23+3 and, importantly, detected an RCC23+3-specific, E-box-binding factor that was distinct from USF and Myc/Mad families. The E-box-mediated repression was also active in normal human fibroblasts and epithelial cells and inactive in some, but not all, telomerase/hTERT-positive cancer cells. These findings provide evidence for an endogenous, repressive mechanism that actively functions in telomerase/hTERT-negative normal cells and becomes defective during carcinogenic processes, e.g., by an inactivation of the telomerase repressor gene on chromosome 3.
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