Telomerase, a ribonucleoprotein complex, extends telomeres, which form the ends of eukaryotic chromosomes. Two major subunits comprise the human telomerase: a structural RNA component (hTR), expressed ubiquitously and the enzymatic reverse transcriptase (hTERT), which catalyzes the de novo synthesis of telomeric repeats onto the chromosome ends. Whereas hTERT activity is quite low and tightly controlled in the majority of normal human cells, about 90% of tumour cells display short telomeres, genomic instability together with an elevated telomerase activity. Thus, activation of hTERT has been considered as an important event in cancer progression. Adult T-cell leukemia (ATL), etiologically linked to a retrovirus, HTLV-1 (Human T-cell Leukemia Virus, type 1), is characterised by a long latency period between an early infection at birth and the emergence, several decades later, of actively proliferating leukemic T cells with a very high telomerase activity.

Our observations are focusing on the role of HBZ (HTLV-1 bZIP factor) a non-structural protein expressed in ATL cells, in upregulating hTERT transcription. It is encoded by the complementary strand of the HTLV-1 genome and has been shown to behave as a co-transcriptional activator through its association with JunD, an AP-1 transcription factor. The presence of AP-1 binding sites in the hTERT distal promoter and their absence in the proximal promoter lead us to investigate the effect of HBZ and JunD in transient transfection assays performed in HeLa cells with specific promoter reporter constructs. Luciferase assays indicate that HBZ or JunD alone did not increase the promoter activity. Conversely, the co-expression of HBZ and JunD was found to correlate with a significant increase of that activity (from 4- to 10-fold, depending on the amount of HBZ). Surprisingly, that synergistic effect was observed not only with the distal promoter containing AP-1 sites, but also with the proximal promoter that contains two E boxes, for fixation of cMyc/Max dimers, and five GC boxes recruiting Sp1 transcription factors. Finally, we have examined the effect of the HBZ and JunD combination on hTERT transcription and detected a 5-fold enhancement of the increase of hTERT transcripts. These results suggest that the viral protein HBZ cooperates with the cellular transcription factor JunD to up-regulate hTERT transcription and telomerase activity in ATL cells.