HTLV-1 HBZ cooperates with JunD to enhance transcription of the human telomerase reverse transcriptase gene (hTERT).
Activation of telomerase is a critical and late event in tumor progression. Thus, in patients with adult-T cell leukaemia (ATL), an HTLV-1 (Human T cell Leukaemia virus type 1)-associated disease, leukemic cells display a high telomerase activity, mainly through transcriptional up-regulation of the human telomerase catalytic subunit (hTERT). The HBZ ... (HTLV-1 bZIP) protein coded by the minus strand of HTLV-1 genome and expressed in ATL cells has been shown to increase the transcriptional activity of JunD, an AP-1 protein. The presence of several AP-1 binding sites in the hTERT promoter led us to investigate whether HBZ regulates hTERT gene transcription.Here, we demonstrate using co-transfection assays that HBZ in association with JunD activates the hTERT promoter. Interestingly, the -378/+1 proximal region, which does not contain any AP-1 site was found to be responsible for this activation. Furthermore, an increase of hTERT transcripts was observed in cells co-expressing HBZ and JunD. Chromatin immunoprecipitation (ChIP) assays revealed that HBZ, and JunD coexist in the same DNA-protein complex at the proximal region of hTERT promoter. Finally, we provide evidence that HBZ/JunD heterodimers interact with Sp1 transcription factors and that activation of hTERT transcription by these heterodimers is mediated through GC-rich binding sites for Sp1 present in the proximal sequences of the hTERT promoter.These observations establish for the first time that HBZ by intervening in the re-activation of telomerase, may contribute to the development and maintenance of the leukemic process.
Mesh Terms:
Basic-Leucine Zipper Transcription Factors, Chromatin Immunoprecipitation, DNA, Dimerization, Human T-lymphotropic virus 1, Humans, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, RNA, Messenger, Sp1 Transcription Factor, Telomerase, Transcription, Genetic, Up-Regulation, Viral Proteins
Basic-Leucine Zipper Transcription Factors, Chromatin Immunoprecipitation, DNA, Dimerization, Human T-lymphotropic virus 1, Humans, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins c-jun, RNA, Messenger, Sp1 Transcription Factor, Telomerase, Transcription, Genetic, Up-Regulation, Viral Proteins
Retrovirology
Date: Dec. 15, 2007
PubMed ID: 18078517
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