HTLV-1 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-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.


RESULTS
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.


CONCLUSIONS
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.
Kuhlmann
Anne-Sophie
AS
Virologie Humaine, INSERM-U758, 69364 Lyon Cedex 07, France. anne-sophie.kuhlmann@ens-lyon.fr
Villaudy
Julien
J
Gazzolo
Louis
L
Castellazzi
Marc
M
Mesnard
Jean-Michel
JM
Duc Dodon
Madeleine
M
D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012191:Retroviridae Proteins; D016329:Sp1 Transcription Factor / Q000378:metabolism; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation; D014764:Viral Proteins / Q000378:metabolism*
D050976:Basic-Leucine Zipper Transcription Factors; C479751:HBZ protein, human T-cell leukemia virus type I; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D012191:Retroviridae Proteins; D016329:Sp1 Transcription Factor; D014764:Viral Proteins; D004247:DNA; C509186:TERT protein, human; D019098:Telomerase