HTLV-I HBZ cooperates with JunD to enhance transcription of the human telomerase reverse transcriptase gene (hTERT)

Background: Activation of telomerase is a critical and late event in tumor progression. Thus, in patients with adult-T cell leukaemia (ATL), an HTLV-I (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-I bZIP) protein coded by the minus strand of HTLV-I genome and expressed in ATL cells has been shown to increase the transcriptional activity of JunD, an AP-I protein. The presence of several AP-I binding sites in the hTERT promoter led us to investigate whether HBZ regulates hTERT gene transcription. Results: Here, we demonstrate using co-transfection assays that HBZ in association with JunD activates the hTERT promoter. Interestingly, the -378/+ I proximal region, which does not contain any AP-I 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 SpI transcription factors and that activation of hTERT transcription by these heterodimers is mediated through GC-rich binding sites for SpI present in the proximal sequences of the hTERT promoter. Conclusion: These observations establish for the first time that HBZ by intervening in the reactivation of telomerase, may contribute to the development and maintenance of the leukemic process.