PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells

Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for l...

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Bibliographic Details
Published in:The Journal of pathology 2010, Vol.220 (1), p.87-96
Main Authors: Bougel, Stéphanie, Renaud, Stéphanie, Braunschweig, Richard, Loukinov, Dmitri, Morse III, Herbert C, Bosman, Fred T, Lobanenkov, Victor, Benhattar, Jean
Format: Article
Language:English
Subjects:
B cells
B-Lymphocytes - enzymology
Base Sequence
Binding Sites
Binding, Competitive
Biological and medical sciences
Cancer
CCCTC-Binding Factor
Cell activation
chromatin immunoprecipitation
CpG Islands - genetics
CTCF
Data processing
DNA Methylation
DNA, Neoplasm - genetics
DNA-directed DNA polymerase
double prime B-cell lymphoma
Fibroblasts
Gene Expression Regulation, Neoplastic
Hematologic and hematopoietic diseases
hTERT
Humans
Investigative techniques, diagnostic techniques (general aspects)
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Lymph nodes
Lymphocytes B
Lymphoid cells
Lymphoma - genetics
Lymphoma - metabolism
Medical sciences
Molecular Sequence Data
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
PAX5
Pax5 protein
PAX5 Transcription Factor - genetics
PAX5 Transcription Factor - metabolism
PAX5 Transcription Factor - physiology
Promoter Regions, Genetic
Promoters
Repressor Proteins - metabolism
Reverse Transcriptase Polymerase Chain Reaction - methods
RNA, Messenger - genetics
RNA, Neoplasm - genetics
RNA, Small Interfering - genetics
Somatic cells
T-cell lymphoma
telomerase
Telomerase - genetics
Telomerase - metabolism
telomerase reverse transcriptase
Transcription activation
Transcription factors
Transcriptional Activation - genetics
Translation
Tumor cell lines
Tumor Cells, Cultured
Tumorigenesis
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Summary:Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA. Its activity is not detectable in most somatic cells but it is reactivated during tumorigenesis. In most cancers, the combination of hTERT hypermethylation and hypomethylation of a short promoter region is permissive for low-level hTERT transcription. Activated and malignant lymphocytes express high telomerase activity, through a mechanism that seems methylation-independent. The aim of this study was to determine which mechanism is involved in the enhanced expression of hTERT in lymphoid cells. Our data confirm that in B cells, some T cell lymphomas and non-neoplastic lymph nodes, the hTERT promoter is unmethylated. Binding sites for the B cell-specific transcription factor PAX5 were identified downstream of the ATG translational start site through EMSA and ChIP experiments. ChIP assays indicated that the transcriptional activation of hTERT by PAX5 does not involve repression of CTCF binding. In a B cell lymphoma cell line, siRNA-induced knockdown of PAX5 expression repressed hTERT transcription. Moreover, ectopic expression of PAX5 in a telomerase-negative normal fibroblast cell line was found to be sufficient to activate hTERT expression. These data show that activation of hTERT in telomerase-positive B cells is due to a methylation-independent mechanism in which PAX5 plays an important role. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN:0022-3417
1096-9896
DOI:10.1002/path.2620