Inactivation of hTERT transcription by Tax

Abstract

Telomerase expression is the hallmark of tumor cells in which this ribonucleoprotein complex preserves chromosome integrity by maintaining telomere length and thereby prevents cell death. However, recent data support a role of the combination of p53 and telomerase inactivation in initiating genetic instability that promotes malignant transformation. Through its pleiotropic effects on infected T-cell metabolism, the human T-cell leukemia virus type 1 (HTLV-1) oncoprotein Tax plays a central role in leukemogenesis. Here, we show that Tax inhibits human telomerase reverse transcriptase (hTERT) transcription, which is the rate-limiting factor of telomerase activity. This inhibitory effect, that occurs in competition with c-Myc through a canonical c-Myc binding site within the hTERT promoter, results in a decreased telomerase activity of Tax-expressing cells. This is the first demonstration of hTERT inhibition by an oncogene. Tax, which is only expressed in preleukemic cells, triggers infected T-cell cycle and keeps these cells cycling while inactivating p53. We propose that, in combination with these effects, hTERT repression by Tax at an early phase of carcinogenesis might contribute to the massive ploidy changes associated with the development of HTLV-1-associated malignancies.

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

“…13,14 It has been established that the Tax transactivator has a negative effect on hTERT expression, whereas the HBZ protein expressed from the reverse strand of the provirus 26 was able to stimulate this expression in combination with JunD. We also observed earlier a cross talk between Tax and TAL1, which mutually reinforced their expression through stimulation of their respective promoters.…”

“…Indeed, it has been reported earlier that Tax inhibits hTERT transcription and that HBZ in combination with JunD activates it. 13,14 It is thought that Tax is highly expressed at early stages of infection before an active immune response blocks expression of the protein. During later stages of infection, several arguments support a very low expression of Tax in ATL cells because of deletion or hypermethylation of the 5 0 LTR and even in some cases to the appearance of stop codons in the Tax coding sequence.…”

“…Indeed, it has been shown that the Tax transactivator decreases the activity of the hTERT promoter through the first E-box. 13 Conversely, the HBZ protein, a factor expressed by the antisense strand of the provirus, activates in cooperation with JunD, the hTERT promoter activity. 14 This led to a model suggesting that early after infection Tax decreases telomerase activity, thereby favoring genomic instability.…”

Current views in HTLV-I-associated adult T-cell leukemia/lymphoma

“…Recent studies demonstrate Tax, through its NF-kB inducing activity, stimulates hTERT expression in HTLV-I-infected cells, allowing maintenance of long telomeres and avoidance of replicative senescence [118]. However, in the presence of antigenic stimulation of T-lymphocytes bearing Tax, hTERT mRNA induction is diminished [118,119]. hTERT is highly inducible in lymphocytes following activation through CD3, possibly to maintain genetic stability of actively dividing cells.…”

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

“…hTERT expression is elevated in most cancer cells and leukemic ATL cells are no exception (Uchida et al, 1999;Tsumuki et al, 2001;Franzese et al, 2002). Interestingly, Tax has been shown to repress transcription from the hTERT promoter during mitogenic stimulation (Gabet et al, 2003), while activating hTERT expression in the absence of mitogenic stimulation (Sinha-Datta et al, 2004). Reduced hTERT expression in response to T-cell stimulation may result in a transient state of genomic instability, which is relieved when the mitogenic stimulus is removed.…”