- Open Access
A balanced transcription between telomerase and the telomeric DNA-binding proteins TRF1, TRF2 and Pot1 in resting, activated, HTLV-1-transformed and Tax-expressing human T lymphocytes
- Emmanuelle Escoffier†1,
- Amélie Rezza†1,
- Aude Roborel de Climens2,
- Aurélie Belleville2,
- Louis Gazzolo1,
- Eric Gilson2 and
- Madeleine Duc Dodon1Email author
© Escoffier et al; licensee BioMed Central Ltd. 2005
Received: 05 October 2005
Accepted: 15 December 2005
Published: 15 December 2005
The functional state of human telomeres is controlled by telomerase and by a protein complex named shelterin, including the telomeric DNA-binding proteins TRF1, TRF2 and Pot1 involved in telomere capping functions. The expression of hTERT, encoding the catalytic subunit of telomerase, plays a crucial role in the control of lymphocyte proliferation by maintaining telomere homeostasis. It has been previously found that hTERT activity is down-regulated by the human T cell leukaemia virus type 1 (HTLV-1) Tax protein in HTLV-1 transformed T lymphocytes. In this study, we have examined the effects of Tax expression on the transcriptional profile of telomerase and of shelterin in human T lymphocytes.
We first provide evidence that the up-regulation of hTERT transcription in activated CD4+ T lymphocytes is associated with a down-regulation of that of TERF1, TERF2 and POT1 genes. Next, the down-regulation of hTERT transcription by Tax in HTLV-1 transformed or in Tax-expressing T lymphocytes is found to correlate with a significant increase of TRF2 and/or Pot1 mRNAs. Finally, ectopic expression of hTERT in one HTLV-1 T cell line induces a marked decrease in the transcription of the POT1 gene. Collectively, these observations predict that the increased transcriptional expression of shelterin genes is minimizing the impact on telomere instability induced by the down-regulation of hTERT by Tax.
These findings support the notion that Tax, telomerase and shelterin play a critical role in the proliferation of HTLV-1 transformed T lymphocytes.
Human telomeres are specialized chromosomal structures that consist of repetitive sequences and a protein complex named shelterin that caps the ends of linear chromosomes [1–3]. Telomeric DNA is mostly composed of double-stranded 5' TTAGGG-3' repeats and terminates with an overhang of single-stranded 3' DNA. In human cells, telomere length is maintained by telomerase (hTERT), a human reverse transcriptase that adds TTAGGG repeats onto the 3' ends of telomeres . hTERT is normally expressed in stem cells and in germ cells, but is present at much reduced levels in many adult somatic cells. As a consequence, loss of telomeric DNA results in replicative senescence through chromosome damage and decrease in cell viability . The shelterin complex is formed by six telomere-specific proteins that provide capping functions and that regulate telomere length . The TRF1, TRF2 and Pot1 subunits bind to telomeric DNA and to the other subunits of the complex, namely the TIN2, TPP1 and Rap1 proteins
Telomerase activity is negatively regulated in vivo, at the level of telomere itself, by several shelterin subunits, including TRF1, TIN2, TPP1, Pot1 and Rap1. For instance, Pot1, a single-stranded telomeric DNA-binding protein, behaves as a terminal transducer of the cis-inhibitory effect of the TTAGGG-repeat-binding protein TRF1 . The shelterin subunit TRF2 [7, 8] is also involved in a negative regulation of telomere lengthening but by cis-activating rapid deletion events within the telomeric tract [9–11]. Although TRF1 and TRF2 do not directly interact, they are engaged in a dynamic complex for telomere length homeostasis .
There is now compelling evidences that telomere modifications seemingly display antagonistic functions in tumorigenesis. On one hand, overexpression of telomerase in cancer cells appears to be crucial for tumor progression thanks to a wealth of studies using mice and cellular models of malignant transformation [13–19]. This is in agreement with the observation that more than 90 % of human tumors overexpress telomerase as compared to the normal matching tissue . On another hand, studies on mice lacking the telomerase RNA gene demonstrate that critical telomere shortening can favor initial stages of cancer formation and cooperates with p53 deficiency to favor carcinogenesis with age [21–23]. In human cells, a burst of telomere instability could also favor tumor formation [21, 24–27].
Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL), which develops after a prolonged period of latency of several decades during which HTLV-1 infected cells proliferate favoring in accumulation of genetic defects and deregulated cell growth [28, 29]. Leukemic CD4+ T cells isolated from patients with ATL have been shown to harbor an elevated telomerase activity [30, 31]. Likewise, a positive correlation has been established between telomerase activity and development and progression of leukemia [32, 33]. Proviral transcription is silent in ATL cells, indicating that viral expression is not directly involved in telomerase activation of ATL cells. We have recently shown that HTLV-1 in vitro infected T cells express a low level of telomerase activity and that this decrease is induced by the viral Tax protein . Tax, a regulatory protein that alters the expression or function of numerous genes involved in the proliferation of T cells, is implicated in the initiation of the leukemogenic process [35–39]. In spite of this low level of telomerase activity, HTLV-1 in vitro infected T cells and Tax-expressing primary T lymphocytes still continue to proliferate, suggesting the induction of a compensatory mechanism.
In the present study, we have examined the transcriptional profile of the genes encoding hTERT, TRF1, TRF2 and Pot1 in normal T lymphocytes as well as in HTLV-1- transformed and in Tax-expressing T lymphocytes. We observed that the physiological activation of CD4+ T lymphocytes induces an up-regulation of hTERT transcription that is correlated with a down-regulation of shelterin subunits (TRF1, TRF2 and Pot1) transcription. Conversely, the down-regulation of hTERT transcription mediated by Tax is associated with an up-regulation of TERF2 and/or POT1 transcription. Furthermore, the ectopic expression of hTERT in HTLV-1 transformed T lymphocytes is sufficient to down-regulate the expression of Pot1. Therefore, these results indicate that in normal as well as in HTLV-1 transformed T lymphocytes and in Tax-expressing lymphocytes, the transcriptional balance between hTERT and the shelterin subunits TRF1, TRF2 and Pot1 are regulating telomere homeostasis and cell proliferation.
Transcriptional expression of hTERT, POT1, TERF1 and TERF2 genes in resting and in vitroactivated CD4+ T lymphocytes
Real-time PCR analysis of hTERT, POT1, TERF1 and TERF2 gene expression upon activation in freshly isolated CD4+ T lymphocytes.
0.43 ± 0.02
10.16 ± 0.02
3.21 ± 0.05
2.08 ± 0.08
0.70 ± 0.09
16.69 ± 8.4
4.24 ± 0.03
Transcriptional expression of hTERT, POT1, TERF1 and TERF2genes in HTLV-1 transformed and Tax-expressing T lymphocytes
Effect of ectopic expression of hTERTin HTLV-1 transformed T lymphocytes on shelterin gene expression
As indicated above, while the overall transcription of the shelterin genes were found to increase in HTLV-1 T cell lines and in Tax-expressing T lymphocytes, the transcription of each shelterin subunit was not affected to a similar extent in each cell type. Thus, the transcription of the POT1 gene was enhanced to a higher level than that of the TERF1 and TERF2 genes in the HTLV-1 T cell lines. Likewise, only TERF2 was found to be up-transcribed in DCH4 cells, whereas the transcription of both TERF2 and POT1 was significantly increased in TSP/HAM cells (Fig. 4, lower panel). It is plausible that these differences might be linked to their in vitro/in vivo derivation and/or to selection pressures in culture. Whatsoever, these data suggest that Tax is not intervening in the modulation of this balanced transcription. Indeed, the observation that Pot1 transcription decreased in C91PL cells over-expressing hTERT implies that the activity of Tax on the telomeric machinery is restricted to its inhibitory effect on hTERT transcription.
Cancer cells commonly up-regulate telomerase, which is consistent with telomerase conferring a strong selective advantage for continued growth of malignant cells . As a matter of fact, telomerase is highly expressed in patients with the acute type of ATL . In these ATL cells, proviral transcription is silent, underlining that viral genome expression is crucial only at the onset of the leukemogenic process. The present study suggests that in infected T cells in which proviral expression is active, the increased expression of TRF2 and/or Pot1, involved in telomere capping functions, could trigger protective mechanisms that compensate the decrease of telomerase expression. Thus, by playing an important role in telomere homeostasis, the shelterin proteins are allowing the proliferation of HTLV-1 infected T cells or Tax-expressing T lymphocytes. Consequently, we anticipate that a transcriptional decrease of these telomeric proteins coupled with telomerase reactivation which might occur at a time, when Tax is no more expressed, would contribute to the emergence of telomerase-positive acute leukemic cells. Interestingly, recent studies have provided new evidence that telomerase enhances expression of growth-controlling genes to confer additional pivotal functions in tumor progression other than telomere length maintenance . Although more work is needed to elucidate the cellular and molecular mechanisms of this telomere dysfunction during the HTLV-1-induced leukemogenic process, the present observations reveal new links between Tax, telomerase and shelterin, that might play a key role in the maintenance and in the proliferation of HTLV-1 infected T lymphocytes.
The HTLV-1 T-cell lines (IL-2 independent) C91PL , MT2 , HUT102  and C8166  have been described elsewhere. The HTLV-1 T-cell lines either (IL-2 dependent) KK1, or (IL-2 independent), MT1 and TLom1 were generously provided by Dr. N. Mori . The DCH4 cells, (kind gift by Dr. D. Derse), were established by transduction of activated, primary human CD4+T cells with a lentivirus vector encoding an HTLV-1 Tax-enhanced yellow fluorescent protein fusion . Three clones of Jurkat T cells stably producing Tax (E12, C11, C50) have been used in this study . T lymphocytes isolated from one TSP/HAM patient (CJ) were kindly provided by Dr. A. Gessain (Paris, France). These lymphocytes and the cell lines KK1 and DCH4 were cultivated in RPMI 1640 (Invitrogen) with 10% heat-inactivated fetal calf serum (FCS) 100 U/ml recombinant human IL-2 (rhIL-2) and supplemented with 100 IU/ml of penicillin and 50 μg/ml of streptomycin. The Jurkat parental as well as the Jurkat Tax-expressing clones, C91PL, MT2, HUT102, MT1 and TLom1 cell lines were maintained in complete RPMI-1640 medium with 10% FCS, without rhIL-2. The human 293T and rhabdomyosarcoma TE cells were cultured in Dulbecco's minimum Eagle medium (DMEM, Invitrogen) supplemented with 10% FCS and antibiotics.
Primary peripheral blood lymphocytes from healthy volunteers were isolated by Ficoll density gradient centrifugation. Then, CD4+ T cell subsets were negatively selected using magnetic beads (Stem Cell Technologies, Vancouver, BC) according to the manufacturer instructions. Purified CD4+ T cells were activated with anti CD3/anti CD28 antibody coated beads (Dynal Biotech, Lake Success, NY) and maintained in RPMI-1640 with 10% FCS and rhIL-2.
Lentiviral constructs and hTERT transduction
The pWPIR-GFP HIV-derived vector, obtained from Didier Trono, contained the IRES-GFP (enhanced GFP as a marker gene) under the control of the EF1 (human elongation factor 1 alpha) promoter . The pWPIR-hTERT-GFP construct was generated by inserting the hTERT cDNA upstream of the IRES in order to allow individual translation of the bicistronic mRNA containing both hTERT and GFP (hTERT-IRES-GFP). Helper-free recombinant lentiviruses were produced after transfection of 293T cells with the three following constructs (1) a packaging plasmid, pCMVR8.91; (2) a transfer vector, pWPIR-hTERT-GFP or pWPIR-GFP; (3) an envelope expression plasmid, pCMV-VSVG. Twenty to 30 hours later, the supernatant was harvested, filtered through a 0.45-μm membrane and aliquots were stored at -80°C. Titres of virus stocks (from 3 to 5 × 105 transducing units per ml) were determined by transduction of human rhabdomyosarcoma TE cells with serially diluted viral supernatant and analysis five days later on a FACScan instrument (Becton Dickinson, Mountain View, CA). C91PL cells cultured for 1–2 hours in presence of polybrene (8 μg/ml) were then incubated overnight with virus supernatant at a multiplicity of infection of 2. Analysis of GFP-expressing cells was performed on a FACScan. Data were analyzed with the Cell Quest program ((Becton Dickinson).
Real-time polymerase chain reaction amplification
Total cellular RNAs were isolated from cells using Qiagen RNeasy purification kits (Qiagen, Alameda, CA) according to the manufacturer's instructions. To reduce the amount of DNA originating from lysis, samples were treated with RNase-free DNase (10 U/μl, Qiagen) for 30 min at 20°C and then for 15 min at 65°C. Five-hundred ng of RNA sample were reverse transcribed by using oligo(dT)12–18 and Superscript II (InVitrogen Life technologies, Frederick, MD). Reverse transcription was performed for 50 min at 42°C. The total cDNA volume of 20 μl was frozen until real-time quantitative PCR was performed. After thawing for PCR experiments, the cDNA was diluted in distilled water and 2 μl of diluted cDNA was used for each PCR reaction. The real-time quantitative PCR (qPCR) was performed in special lightcycler capillaries (Roche) with a lightcycler Instrument (Roche), by using the LightCycler-FastStart reaction Mix SYBR-Green kit (Roche). The following specific primers were used to detect: PBGD, sense 5'-GGAATGCATGTATGCTGTGG-3' and antisense, 5'-CAGGTACAGTTGCCCATCC-3', TaxHTLV-1sense, 5'-GTTGTATGAGTGATTGGCGGGGTAA-3' and antisense, 5'-TGTTTGGAGACTGTGTACAAGGCG-3', hTERT sense, 5'-TGTTTCTGGATTTGCAGGTG-3' and antisense, 5'-GTTCTTGGCTTTCAGGATGG-3', Pot1 sense, 5'-TGGGTATTGTACCCCTCCAA-3' and antisense, 5'-GATGAAGCATTCCAACCACGG-3'. TRF1 sense,5'-GCTGTTTGTATGGAAAATGGC-3' and antisense: 5'-CCGCTGCCTTCATTAGAAAG-3', TRF2 sense, 5'-GACCTTCCAGCAGAAGATGC-3' and antisense, 5'-GTTGGAGGATTCCGTAGCTG-3'. The thermal cycling conditions consisted of 40 cycles at 95°C for 10 sec, 61°C for 5 sec, 72°C for 10 sec. The fluorescence signal increase of SYBR-GREEN was automatically detected during the 72°C phase of the PCR. Omission of reverse transcriptase in the RT-PCR protocol led to a failure of target gene amplification in the positive controls. Light cycler PCR data were analyzed using LightCycler Data software (Idaho Technology). The software first normalizes each sample by background subtraction of initial cycles. A fluorescence threshold is then set at 5% full scale, and the software determines the cycle number at which each sample reached this threshold. The fluorescence threshold cycle number correlates inversely with the log of initial template concentration. A standard calibration curve was performed by using cDNA from Jurkat cells. The levels of PBGD transcripts were used to normalize the amount of cDNA in each sample.
We thank D. Derse, N. Mori and A. Gessain for providing cells. This study was supported by ARC (Association pour la Recherche sur le Cancer n°5669 to LG.), by the Ligue Nationale contre le Cancer (to EG) and by EPIMED program of the Cancéropole Lyon Auvergne Rhône-Alpes (CLARA).
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