Transcriptional activation of hTERT through the NF-κB pathway in HTLV-I–transformed cells
| Autor: | Izumi Horikawa, Abhik Datta, Mirdad Kazanji, Janitzia C. Sigler-Nicot, J. Carl Barrett, Christophe Nicot, Eriko Michishita, Uma Sinha-Datta, Megan Brown |
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| Rok vydání: | 2004 |
| Předmět: |
Transcriptional Activation
Telomerase Transcription Genetic Sp1 Transcription Factor T-Lymphocytes Immunology Biology Lymphocyte Activation medicine.disease_cause Biochemistry Proto-Oncogene Proteins c-myc medicine Humans Leukemia-Lymphoma Adult T-Cell Telomerase reverse transcriptase RNA Messenger Promoter Regions Genetic Cells Cultured Cell Line Transformed Human T-lymphotropic virus 1 Models Genetic ZAP70 NF-kappa B Gene Products tax Cell Biology Hematology Transfection Virology Chromatin Reverse transcriptase Telomere DNA-Binding Proteins Cancer research Carcinogenesis Chromatin immunoprecipitation |
| Zdroj: | Blood. 104:2523-2531 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2003-12-4251 |
| Popis: | In immortal cells, the existence of a mechanism for the maintenance of telomere length is critical. In most cases this is achieved by the reactivation of telomerase, a cellular reverse transcriptase that prevents telomere shortening. Here we report that the telomerase gene (hTERT) promoter is up-regulated during transmission of human T-cell lymphotropic virus type-I (HTLV-I) to primary T cells in vitro and in ex vivo adult T-cell leukemia/lymphoma (ATLL) samples, but not asymptomatic carriers. Although Tax impaired induction of human telomerase reverse transcriptase (hTERT) mRNA in response to mitogenic stimulation, transduction of Tax into primary lymphocytes was sufficient to activate and maintain telomerase expression and telomere length when cultured in the absence of any exogenous stimulation. Transient transfection assays revealed that Tax stimulates the hTERT promoter through the nuclear factor κB (NF-κB) pathway. Consistently, Tax mutants inactive for NF-κB activation could not activate the hTERT or sustain telomere length in transduced primary lymphocytes. Analysis of the hTERT promoter occupancy in vivo using chromatin immunoprecipitation assays suggested that an increased binding of c-Myc and Sp1 is involved in the NF-κB–mediated activation of the hTERT promoter. This study establishes the role of Tax in regulation of telomerase expression, which may cooperate with other functions of Tax to promote HTLV-I–associated adult T-cell leukemia. |
| Databáze: | OpenAIRE |
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