Back to Search
Start Over
Transcriptional activation of hTERT through the NF-kappaB pathway in HTLV-I-transformed cells.
- Source :
-
Blood [Blood] 2004 Oct 15; Vol. 104 (8), pp. 2523-31. Date of Electronic Publication: 2004 Jun 29. - Publication Year :
- 2004
-
Abstract
- 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 kappaB (NF-kappaB) pathway. Consistently, Tax mutants inactive for NF-kappaB 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-kappaB-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.
- Subjects :
- Cell Line, Transformed
Cells, Cultured
Chromatin genetics
Chromatin metabolism
DNA-Binding Proteins
Gene Products, tax genetics
Humans
Leukemia-Lymphoma, Adult T-Cell enzymology
Leukemia-Lymphoma, Adult T-Cell genetics
Leukemia-Lymphoma, Adult T-Cell virology
Lymphocyte Activation drug effects
Models, Genetic
Promoter Regions, Genetic genetics
Proto-Oncogene Proteins c-myc metabolism
RNA, Messenger genetics
RNA, Messenger metabolism
Sp1 Transcription Factor metabolism
T-Lymphocytes cytology
T-Lymphocytes drug effects
T-Lymphocytes metabolism
T-Lymphocytes virology
Telomerase metabolism
Gene Products, tax metabolism
Human T-lymphotropic virus 1 physiology
NF-kappa B metabolism
Telomerase genetics
Transcription, Genetic genetics
Transcriptional Activation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 104
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 15226182
- Full Text :
- https://doi.org/10.1182/blood-2003-12-4251