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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Patterson, Tricia Feigenbaum, Lionel Chiang, Y. Jeffrey Horikawa, Izumi Michishita, Eriko Leem, Sun-hee Hodes, Richard J. Barrett, J. Carl Larionov, Vladimir |
| Description | Author Affiliation: Horikawa I ( Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. horikawi@mail.nih.gov); |
| Abstract | In vivo expression of human telomerase is significantly different from that of mouse telomerase. To assess the basis for this difference, a bacterial artificial chromosome clone containing the entire hTERT (human telomerase reverse transcriptase) gene was introduced in mice. In these transgenic mice, expression of the hTERT transgene was similar to that of endogenous hTERT in humans, rather than endogenous mTERT (mouse telomerase reverse transcriptase). In tissues and cells showing a striking difference in expression levels between hTERT in humans and mTERT in mice (i.e., liver, kidney, lung, uterus, and fibroblasts), expression of the hTERT transgene in transgenic mice was repressed, mimicking hTERT in humans. The transcriptional activity of the hTERT promoter was much lower than that of the mTERT promoter in mouse embryonic fibroblasts or human fibroblasts. Mutational analysis of the hTERT and mTERT promoters revealed that a nonconserved GC-box within the hTERT promoter was responsible for the human-specific repression. These results reveal that a difference in cis-regulation of transcription, rather than transacting transcription factors, is critical to species differences in tissue-specific TERT expression. Our data also suggest that the GC-box-mediated, human-specific mechanism for TERT repression is impaired in human cancers. This study represents a detailed characterization of the functional difference in a gene promoter of mice versus humans and provides not only important insight into species-specific regulation of telomerase and telomeres but also an experimental basis for generating mice humanized for telomerase enzyme and its pattern of expression. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 51 |
| Volume Number | 102 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2005-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | DNA-Binding Proteins Genetics Down-Regulation Telomerase Animals Cell Line, Tumor Metabolism Mice Mice, Transgenic Molecular Sequence Data Neoplasms Enzymology Promoter Regions, Genetic Response Elements Species Specificity Transcription, Genetic Comparative Study Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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