Inhibition of the hTERT promoter by the proto-oncogenic protein TAL1

Abstract

Telomerase activity, which has fundamental roles in development and carcinogenesis, strongly depends on the expression of human telomerase reverse transcriptase (hTERT), its catalytic subunit. In this report, we show that the basic helix-loophelix factor, TAL1 (T-cell acute lymphoblastic leukemia 1), is a negative regulator of the hTERT promoter. Indeed, TAL1 overexpression leads to a decrease in hTERT mRNA abundance and hence to reduced telomerase activity. Conversely, suppression of TAL1 by RNA interference in Jurkat cells increases hTERT expression. Analysis by chromatin immunoprecipitation assays showed that TAL1 binds to the hTERT proximal promoter and recruits HDAC1. Considering the relationship recently established between TAL1 and the human T-cell leukemia virus type 1 (HTLV-1) Tax protein, which was confirmed in T lymphocyte clones derived from adult T-cell leukemia patients, we analyzed the effect of TAL1 with respect to the earlier characterized effects of Tax and HBZ (HTLV-1 basic leucine zipper) on hTERT expression. TAL1 was observed to reinforce the negative effect of Tax, whereas hTERT transactivation by the HBZ-JunD complex was repressed by TAL1 overexpression. Moreover, HBZ was found to induce proteasome-mediated degradation of TAL1. These observations support a model in which Tax and TAL1 by repressing hTERT would initially favor genomic instability, whereas expression of factors such as HBZ allows at a later stage an increase in hTERT production and consequently in telomerase activity.

Multifaceted functions and roles of HBZ in HTLV-1 pathogenesis

“…HBZ has been reported to promote human TERT (hTERT) expression via enhancing its promoter activity in association with JunD [ 68 ]. The activities of two inhibitors of the hTERT promoter, TAL1 and menin, are also suppressed by HBZ [ 69 , 70 ]. Elevation of hTERT levels by HBZ may allow sustained proliferation of ATL cells, which have been reported to overexpress hTERT [ 71 , 72 ].…”

The proto-oncogenic protein TAL1 controls TGF-β1 signaling through interaction with SMAD3

“…4 C, lanes 3 and 4). We previously reported that TAL1 was able to negatively regulate the promoter of the protein subunit of the telomerase enzyme [25] . By testing the effect of SMAD3 on the hTERT promoter we also observed a dose dependent negative effect ( Fig.…”

“…Plasmids used in this study have been previously described: pSGF-TAL1 [24] , pSG5-MYC-TAL1 [25] and pSG-HA-Ub [26] . pCMV-Flag-E47 was kindly provided by C. Gallego [27] .…”

Aspects virologiques de l’infection par HTLV-1 et nouveaux concepts thérapeutiques

“…L'expression d'HBZ augmente en particulier l'activité transcriptionnelle de JunD sur le gène hTERT, codant la sous-unité catalytique de la télomérase. HBZ induit par ailleurs la dégradation par le protéasome de TAL1 (T-cell acute lymphoblastic leukemia 1), un régulateur négatif du promoteur de hTERT [32]. Ces résultats indiquent que l'activité télomérase élevée observée chez les patients souffrant d'ATLL est, en partie du moins, la conséquence de ces rôles convergents d'HBZ [18].…”