Transcriptional activation of hTERT through the NF-kappaB pathway in HTLV-I-transformed cells.
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.
Sinha-Datta
Uma
U
University of Kansas Medical Center, Department of Microbiology, Immunology, and Molecular Genetics, 3025 Wahl Hall West, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
Horikawa
Izumi
I
Michishita
Eriko
E
Datta
Abhik
A
Sigler-Nicot
Janitzia C
JC
Brown
Megan
M
Kazanji
Mirdad
M
Barrett
J Carl
JC
Nicot
Christophe
C
D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000201:enzymology / Q000235:genetics / Q000821:virology; D008213:Lymphocyte Activation / Q000187:drug effects; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
D002843:Chromatin; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D019098:Telomerase