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Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, Ishikawa 920-0934, Japan [M. T., S. K., T. K., M. I.]; Nippon Gene Co., Ltd., Enzyme Research Laboratory Toyama 930-0854, Japan, [H. H.]; Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan [J. T.]; and Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan [M. Y.]
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ABSTRACT |
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Introduction |
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Recently, three major subunits comprising the human telomerase complex have been identified. The RNA component of human telomerase (hTR) provides the template for telomere repeat synthesis (10) . Several studies have shown that disrupting the function of telomerase RNA leads to progressive shortening of telomeres, suggesting that this component plays an essential role in telomerase function (11) . Most recently, targeting the telomerase RNA gene in mice has been shown to lead to progressive shortening of telomeres and to impair long-term viability of tissues with high rates of renewal such as testis and bone marrow (12 , 13) . Three proteins in different species associated with telomerase activity have also been identified. p80 and p95 were purified from the ciliate Tetrahymena (14) , and the gene encoding a mammalian homologue of p80, TP1/TLP1, has also been cloned (15 , 16) . The functional significance of these telomerase-associated proteins remains unclear. Two related proteins, Est2p and p123, have been newly identified as catalytic subunits of telomerase in the yeast Saccharomyces cerevisiae and the ciliate Euplotes aediculatus, respectively. These proteins harbor several sequence motifs characteristic of catalytic regions of reverse transcriptase (17 , 18) . Disruption of these motifs has been shown to abolish enzymatic activity of telomerase. Most recently, the human homologue of Est2p and p123 has been cloned (hTERT; Refs. 19 and 20 ). Expression of hTERT is observed at high levels in malignant tumors and cancer cell lines but not in normal tissues or telomerase-negative cell lines, and a strong correlation was found between hTERT expression and telomerase activity in a variety of tumors such as cervical cancer, urothelial cancer, and renal cell carcinomas (21, 22, 23) . Introduction of hTERT cDNA into normal cells confers telomerase activity in these cells (24 , 25) . hTERT-expressing normal cell clones have an extended life span without any change in karyotypes (26) . These findings strongly suggest that hTERT is a catalytic subunit homologue protein of human telomerase, and that up-regulation of hTERT might be a critical event in carcinogenesis.
Despite these findings, the molecular mechanisms by which hTERT is expressed remain to be determined. This is mainly due to the lack of information on transcriptional regulation of the hTERT gene. Identification of promoter sequences and transcription factors essential for transcriptional regulation of the hTERT gene may greatly contribute to understanding of molecular mechanisms of telomerase regulation. In the present study, we cloned the 5'-flanking sequence of hTERT and identified the core promoter region essential for transcriptional activation in immortalized and cancer cells.
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Materials and Methods |
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Cloning of Sequences Encompassing the Human Telomerase Reverse Transcriptase Genes.
To identify an hTERT genomic clone, a human genomic library in Lambda Fix II (Stratagene) was screened with a 32P-labeled hTERT cDNA fragment that contained 600 bp of 5'-hTERT cDNA sequences. Screening of 500,000 plaques yielded one positive clone (TM-1) with a 5.6-kb insert. After three rounds of screening, TM-1 was plaque purified, subcloned into pGEM-3zf(+) (Stratagene), sequenced with a dRhodamine Terminator Cycle Sequencing FS Ready Reaction kit (ABI), and analyzed on an ABI Model 377 automated DNA sequencer. The nucleotide sequence data reported in this paper will appear in the DDBJ/EMBL/GenBank nucleotide sequences with the accession number AB016767.
Determination of Transcription Start Site.
To determine the transcription start site of hTERT mRNA, a CapSite Hunting method was used in accordance with the manufacturer’s protocol (Nippon Gene, Tokyo, Japan). Briefly, mRNAs from HeLa cells were isolated, and the 5'-terminal m7GpppN cap structure was removed by the pyrophosphorolysis reaction of tobacco nucleotide acid pyrophosphatase and recapped with the 3'end of a 38 mer-specific oligonucleotide (rOligo) by an RNA ligase reaction. A single-strand cDNA library was prepared from the recapped mRNA by the synthesis of first-strand cDNA with Moloney murine leukemia virus reverse transcriptase and random primer. To amplify hTERT-specific transcripts from the single-strand DNA library, nested PCR was performed using specific primers corresponding to the 38-mer rOligo and the 5'cDNA sequence of hTERT between 63 and 84 (5'-CACGAACGTGGCCAGCGGCAGC-3') for the first-round PCR and between 42 and 65 (5'-AGCACCTCGCGGTAGTGGCTGCGC-3') for the second round PCR. Single bands of second round PCR products were isolated and subcloned into pGEM, and three independent clones were sequenced. The transcription start site was determined by identification of the boundary sequence between rOligo and hTERT mRNA sequences.
Plasmid Construction.
The structures of hTERT promoter-luciferase constructs are shown in Figs. 3
and 7
. Various lengths of DNA fragments upstream of the initiating ATG codon were PCR amplified and inserted into luciferase reporter vector pGL3-Basic, a promoter- and enhancerless vector (Promega) in sense orientation relative to the luciferase coding sequence at MluI and BglII sites. For the construction of reporter plasmids containing substitution mutations in factor binding sites, site-specific mutagenesis was performed by a PCR-based protocol (27)
. The sequence of each insert was checked by sequencing. The name of each reporter construct was assigned according to the 5'-end nucleotide numbers of inserted promoter sequences, upstream (-) or downstream (+) of transcription start site. c-Myc expression vector (pEF-Myc) was kindly provided by Dr. H. Ariga (Hokkaido University, Sapporo, Japan), in which c-Myc cDNA is driven by elongation factor promoter.
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TRAP Assay.
TRAP assay was performed as described previously with some modifications (6)
. Cell pellets were washed in PBS and homogenized in ice-cold lysis buffer [10 mM Tris-HCl (pH 7.5), 1 mM MgCl2, 1 mM EGTA, 0.1 mM phenylmethylsulfonyl fluoride, 5 mM ß-mercaptoethanol, 0.5% 3-[3-cholamidopropyl)dimethylamino]-1-propanesulfonate (Sigma), and 10% glycerol]. After 30 min of incubation on ice, the lysate was centrifuged, and the supernatants were recovered. Assay tubes were prepared by sequestering 0.2 µg of CX primer (6)
under a wax barrier (Ampliwax; Perkin-Elmer Cetus, Foster City, CA). Two µg of protein extracts were assayed in 50 µl of reaction mixture containing 20 mM Tris-HCl (pH 8.0), 1.5 mM MgCl2, 60 mM KCl, 0.005% Tween 20, 1 mM EGTA, 50 µM deoxynucleotide triphosphates, 0.2 µg of TS primer (6)
, 1 µg of T4g 32 protein (Boehringer Mannheim), and 2.5 units of Taq DNA polymerase (Wako, Osaka, Japan). After 30 min incubation at 23°C, the reaction mixture was heated at 90°C for 3 min and then subjected to 31 cycles of PCR including denaturation at 94°C for 45 s, annealing at 50°C for 45 s, and extension at 72°C for 60 s. The PCR products were electrophoresed on a 12% polyacrylamide gel and visualized with SYBR Green I Nucleic Acid Gel Stain (FMC, BioProducts, Rockland, ME).
Gel Shift Assay.
Nuclear extracts were prepared from C33A cells as described previously (28)
. Five µg of proteins were incubated with 1 µg of poly(deoxyinosinic-deoxycytidylic acid) in the presence or absence of a 100-fold molar excess of unlabeled competitor DNAs on ice for 20 min in a 25-µl reaction volume containing 10% glycerol, 25 mM HEPES (pH 7.9), 50 mM KCl, 0.5 mM phenylmethylsulfonyl fluoride, and 1 mM DTT. For supershift assay, specific antibodies against transcription factors were preincubated with nuclear extracts at 4°C for 60 min. After incubation, 20,000 c.p.m of 32P end-labeled oligonucleotide probes were added, and the reaction was incubated at 4°C for an additional 30 min. The DNA-protein complexes were then separated from free probes by electrophoresis on a 4% polyacrylamide gel. The gel was dried and subjected to autoradiography. For competition assays, consensus oligonucleotides for AP1 (5'-CGCTTGATGAGTCAGCCGGAA-3'; Promega), AP2 (5'-GATCGAACTGACCGCCCGCGGCCCGT-3'; Promega), Sp1 (5'-ATTCGATCGGGGCGGGGCGAGC-3'; Promega), Myc/Max (5'-GGAAGCAGACCACGTGGTCTGCTTCC-3'; Santa Cruz Biotechnology), and mutant oligonucleotides for Myc/Max (5'-GGAAGCAGACCACGGAGTCTGCTTCC-3'; Santa Cruz Biotechnology) were used as competitors. The antibodies against c-Myc and Max were kindly provided by Dr. H. Ariga (Hokkaido University, Sapporo, Japan). The Sp1 antibody was purchased from Santa Cruz Biotechnology.
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Results |
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5.5 kb genomic clone (TM-1) encompassing 2135-bp genomic sequences of the hTERT gene including exon 1 (275 bp) and exon 2 (1355 bp) as well as the 3347-bp 5'-flanking sequence of hTERT gene was isolated (Fig. 1)
. Use of the CapSite Hunting method showed that the transcription start site is 77 bp upstream of the initiating ATG (Fig. 2)
. The first base in the mRNA is labeled +1, and the first base of the promoter is labeled -1 (Fig. 1)
. The 5'-flanking sequence with the first 200 bp is rich in GC content and lacks the typical TATA-box motif. A putative initiator element, which is thought to be strongly required for transcription initiator activity of TATA-less promoter, was found at position -3 (CCTCTCC), which conforms well with a consensus initiator sequence PyPyANA/TPyPy. Several potential transcription factor binding sites were found in this region, such as Sp1 consensus (GGGCGG) at positions -7 and -88, as well as their degenerated motifs at -36, -56, and -110. There were also several consensus motifs for AP2 and GC factor. Interestingly, two E boxes (CACGTG) were found at positions -165 and 44.
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) and transfected into cervical cancer cell lines C33A, HeLa, ME180, and SiHa, all of which were confirmed to be telomerase positive (data not shown), as well as normal primary keratinocytes and fibroblasts derived from skin, which lack telomerase activity, and the cell lysates were tested in luciferase assays. As shown in Fig. 4A,
a 1.4 kb region (pGL3–1375) demonstrated significant transcriptional activity in these cancer cell lines. In particular, C33A and ME180 cells conferred the highest transcriptional activity, comparable with that in control reporter plasmids (pGL3-Control) driven by SV40 enhancer/promoter. HeLa and SiHa cells exhibited modest transcriptional activities equivalent to 10–20% of positive control activity, but these activities were still significant, because they were 100-fold the activity in promoter-less reporter plasmid (pGL3-basic). In contrast, neither normal primary keratinocytes nor normal primary fibroblasts conferred demonstrable transcriptional activity (Fig. 4B)
. These findings suggest that hTERT transcription is significantly activated in cancer cells but not in normal cells.
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. Luciferase assays were performed to observe changes in transcriptional activity during the malignant progression of RB cells. As shown in Fig. 5
, primary RB cells in early generations did not confer significant transcriptional activity. Transcriptional activity was also repressed in the strains (RBSV) that obtained increased proliferative capacity and had extended life span due to transfection with SV40 LT but still underwent replicative senescence. In contrast, it was dramatically up-regulated in clones (RBI) that had overcome replicative senescence and obtained characteristics of immortality. The clones with anchorage-independent growth (RBS) and tumorigenicity in mice (RBT) also conferred significant transcriptional activity to a greater extent than did RBI cells. Interestingly, the levels of transcription increased with malignant progression of this lineage. Telomerase activity in this lineage was simultaneously examined, and the telomeric repeat amplification protocol assay revealed that RB and RBSV cells did not exhibit telomerase activity, whereas RBI, RBS, and RBT cells demonstrated significant telomerase activity.
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. As shown in Fig. 4
, transcriptional activity in C33A and ME180 cells decreased with 5' truncations, and the 776-bp fragment exhibited the minimal activity. However, transcriptional activity increased with more extended truncations, and the proximal 181-bp fragment conferred peak transcriptional activity, equivalent to 60–80% of control activity in the pGL3-Control. Truncations of this fragment (pGL-82 and pGL-31) resulted in a stepwise decrease in transcriptional activity, but the proximal 31-bp fragment still conferred the significant transcriptional activity. To exclude the possibility that sequences downstream of the transcription start site participate in transcriptional regulation, we tested a reporter plasmid containing untranslated downstream sequences (pGL3+19), but it did not exhibit transcriptional activity, suggesting that these sequences do not function as a part of the core promoter. Similar findings were observed for HeLa and SiHa cells, except that overall transcriptional activities are lower than for C33A and ME180 cells. In contrast, in normal primary keratinocytes and fibroblasts, no significant transcriptional activity was observed in either 1.4 kb or 5'-truncated fragments of hTERT promoter. These findings suggest that the proximal 181-bp region upstream of the transcription start site functions as the core promoter essential for transcriptional activation of hTERT.
Identification of Nuclear Factors Binding Core Promoter Region.
To identify the transcription factors that bind the proximal core promoter, gel shift assays were performed using nuclear extracts from C33A cells. A total of seven pobes were prepared to cover the entire region of core promoter as shown in Fig. 1
. Using probe 1 containing E box (CACGTG) at position -165, a significant retarded band was observed, which was completely competed by addition of homologous competitors, but not those with substitution mutations in the E box. It was also competed by the addition of Myc/Max consensus oligonucleotides but not by Myc/Max mutant oligonucleotides or unrelated oligonucleotides (Fig. 6)
. However, neither competition nor supershift of the band was observed by addition of Myc or Max antibody (data not shown). As shown in Fig. 1
, another E box is located at position 44 in 5' untranslated region. Gel shift assay using this E box region as probe yielded the similar results .
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Activation of hTERT Transcription by c-Myc.
Recently, c-Myc has been reported to activate telomerase in normal epithelial and fibroblast cells through up-regulation of hTERT (28)
. To elucidate the mechanism of hTERT up-regulation by Myc, c-Myc was overexpressed in several cell lines as well as normal primary cells, and luciferase assays were performed. In SiHa cells, introduction of c-Myc expression vectors resulted in more than 3-fold activation of hTERT transcription in pGL3-1375 (Fig. 7)
. In HeLa and normal human renal cortical cells, more than 2-fold activation was observed. Similar results were obtained using the core promoter reporter plasmid (pGL3-181). These findings suggest that c-Myc interacts with core promoter to activate hTERT transcription.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Analysis of 5'-truncations of the promoter revealed that transcriptional activity decreased with deletion of sequences between -776 and -1375 and increased with the deletion of sequences between -378 and -776. These findings suggest that cis-acting and silencer elements, respectively, may exist in these regions. One important question is whether the potential silencer between -378 and -776 causes low transcriptional activity in normal cells. In normal cells, the proximal 181-bp region that lacks this silencer did not confer transcriptional activity, comparable with that in tumor cells. Therefore, the low transcriptional activity in normal cells is not simply explained by the action of this silencer. Transcriptional activity dramatically decreased with truncation of the 181-bp proximal region, and the untranslated downstream sequences did not contribute to transcriptional activity. These findings suggest that the 181-bp fragment upstream of the transcription start site is a core functional promoter essential for transcriptional activation of hTERT in cancer cells.
As shown in the present study, the promoter sequence of hTERT lacked a TATA box and TATA-like sequence. TATA-less promoters are frequently described as housekeeping genes, although hTERT is specifically up-regulated in tumors. TATA-less promoters often contain GC-rich regions in the proximal promoter (30) , and an initiator element is usually found around the transcription start site. The promoter of hTERT conforms with this model. In the absence of a TATA box, it has been postulated that an initiator element helps position the RNA polymerase II and locate a transcription start site (31) . In the hTERT promoter, an initiator-like sequence (CCTCTCC) was found around the transcription start site at position -3. It has also been demonstrated that TATA-less promoters still use TATA factors, and several factors have been proposed to help initiate transcription from TATA-less genes (31) . In the present gel shift assay, we found that Sp1 binds at least five sites in the hTERT core promoter. It has been reported that Sp1 tethers the TATA factors and plays significant roles in transcriptional initiation (30) . Sp1 might thus be one of the critical factors promoting initiation of hTERT transcription. Although Sp1 is known to be a ubiquitous factor, it has been shown to be up-regulated in fetal tissues, sperm, and hematopoietic cells in human early development, all of which are known to exhibit elevated levels of telomerase activity (32) . It will thus be important to compare the levels of Sp1 expression between tumors and normal tissues.
Another factor we identified on gel shift assay is the E box binding factor. Several factors are known to bind the E box, such as Myc-related family members TFE3 and USF. In our competition assays, the retarded band on probe 1 was competed by Myc/Max consensus oligonucleotides. However, in the supershift assay, the band was not competed or supershifted by addition of Myc or Max antibody. These findings suggest that factor(s) other than Myc/Max heterodimer, which can recognize Myc/Max consensus motif, binds this E box. Because E box binding proteins are known to heterodimerize with a variety of factors with a bHLH3 leucine zipper domain (bHLH-Zip), careful biochemical analysis will be required to identify the factors binding this site. Recently, c-Myc has been reported to activate telomerase in normal epithelial and fibroblast cells through up-regulation of hTERT (28) . In the present study, overexpression of c-Myc resulted in significant activation of hTERT transcription in normal and cancer cells. These findings suggest that up-regulation of telomerase by Myc is conferred through transactivation of hTERT. Our gel shift assay using C33A nuclear extracts failed to reveal Myc binding in the E box. However, we have not examined the ability of purified Myc to bind this site, and it is still possible that overexpressed c-Myc recognizes this site in vivo, competing with factor(s) we identified in gel shift assay. Although c-Myc homodimerizes and binds DNA poorly, it preferentially heterodimerizes with Max, its exclusive dimerization partner interacting through the COOH-terminal bHLH zipper domain (bHLH-Zip; Ref. 33 ). Recently described members of this bHLH-Zip gene family are those of the Mad family, which form heterodimeric complexes with Max that have opposing effects to Myc-Max heterodimers (34 , 35) . The function of Myc/Max complex is thus mediated by switches in the dimerization partners. We are presently investigating whether this switching function regulates hTERT transcription.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Kanazawa University, 31-1 Takaramachi, Kanazawa, Ishikawa 920, Japan. Phone: 81-762-265-2425; Fax: 81-762-234-4266; E-mail: satoruky{at}med.kanazawa-u.ac.jp 
2 K. Oka, Y. Tomonaga, T. Nakazawa, H. Y. Gao, U. Bengtsteen, E. J. Stanbridge, N. Yoshioka, Q. Li, A. Hakura, and M. Yutsudo. Malignant transformation of human diploid fibroblasts and suppression of its anchorage independency by introduction of chromosome 13, submitted for publication.
3 The abbreviation used is: bHLH, basic helix-loop-helix.
Received 8/13/98. Accepted 12/16/98.
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 Y. Matsumura-Arioka, K. Ohtani, T. Hara, R. Iwanaga, and M. Nakamura Identification of two distinct elements mediating activation of telomerase (hTERT) gene expression in association with cell growth in human T cells Int. Immunol., February 1, 2005; 17(2): 207 - 215. [Abstract] [Full Text] [PDF]
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I. Shats, M. Milyavsky, X. Tang, P. Stambolsky, N. Erez, R. Brosh, I. Kogan, I. Braunstein, M. Tzukerman, D. Ginsberg, et al. p53-dependent Down-regulation of Telomerase Is Mediated by p21waf1 J. Biol. Chem., December 3, 2004; 279(49): 50976 - 50985. [Abstract] [Full Text] [PDF]
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 U. Sinha-Datta, I. Horikawa, E. Michishita, A. Datta, J. C. Sigler-Nicot, M. Brown, M. Kazanji, J. C. Barrett, and C. Nicot Transcriptional activation of hTERT through the NF-{kappa}B pathway in HTLV-I-transformed cells Blood, October 15, 2004; 104(8): 2523 - 2531. [Abstract] [Full Text] [PDF]
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S. C. Verma, S. Borah, and E. S. Robertson Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Up-Regulates Transcription of Human Telomerase Reverse Transcriptase Promoter through Interaction with Transcription Factor Sp1 J. Virol., October 1, 2004; 78(19): 10348 - 10359. [Abstract] [Full Text] [PDF]
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 L. Gewin, H. Myers, T. Kiyono, and D. A. Galloway Identification of a novel telomerase repressor that interacts with the human papillomavirus type-16 E6/E6-AP complex Genes & Dev., September 15, 2004; 18(18): 2269 - 2282. [Abstract] [Full Text] [PDF]
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Q. Zhang, M. Nie, J. Sham, C. Su, H. Xue, D. Chua, W. Wang, Z. Cui, Y. Liu, C. Liu, et al. Effective Gene-Viral Therapy for Telomerase-Positive Cancers by Selective Replicative-Competent Adenovirus Combining with Endostatin Gene Cancer Res., August 1, 2004; 64(15): 5390 - 5397. [Abstract] [Full Text] [PDF]
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 K. T. Smith, B. Coffee, and D. Reines Occupancy and synergistic activation of the FMR1 promoter by Nrf-1 and Sp1 in vivo Hum. Mol. Genet., August 1, 2004; 13(15): 1611 - 1621. [Abstract] [Full Text] [PDF]
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 Q. Huang, X. Zhang, H. Wang, B. Yan, J. Kirkpatrick, M. W. Dewhrist, and C.-Y. Li A Novel Conditionally Replicative Adenovirus Vector Targeting Telomerase-Positive Tumor Cells Clin. Cancer Res., February 15, 2004; 10(4): 1439 - 1445. [Abstract] [Full Text] [PDF]
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H. Yang, C. C. Ou, R. I. Feldman, S. V. Nicosia, P. A. Kruk, and J. Q. Cheng Aurora-A Kinase Regulates Telomerase Activity through c-Myc in Human Ovarian and Breast Epithelial Cells Cancer Res., January 15, 2004; 64(2): 463 - 467. [Abstract] [Full Text] [PDF]
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B. S. Goueli and R. Janknecht Upregulation of the Catalytic Telomerase Subunit by the Transcription Factor ER81 and Oncogenic HER2/Neu, Ras, or Raf Mol. Cell. Biol., January 1, 2004; 24(1): 25 - 35. [Abstract] [Full Text] [PDF]
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T. Fukazawa, Y. Maeda, F. M. Sladek, and L. B. Owen-Schaub Development of a Cancer-Targeted Tissue-Specific Promoter System Cancer Res., January 1, 2004; 64(1): 363 - 369. [Abstract] [Full Text] [PDF]
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A. Takahashi, F. Higashino, M. Aoyagi, K. Yoshida, M. Itoh, S. Kyo, T. Ohno, T. Taira, H. Ariga, K. Nakajima, et al. EWS/ETS Fusions Activate Telomerase in Ewing's Tumors Cancer Res., December 1, 2003; 63(23): 8338 - 8344. [Abstract] [Full Text] [PDF]
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 A. Ohali, S. Avigad, I.J. Cohen, I. Meller, Y. Kollender, J. Issakov, I. Gelernter, Y. Goshen, I. Yaniv, and R. Zaizov Association Between Telomerase Activity and Outcome in Patients With Nonmetastatic Ewing Family of Tumors J. Clin. Oncol., October 15, 2003; 21(20): 3836 - 3843. [Abstract] [Full Text] [PDF]
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 T. Takeda, H. Inaba, M. Yamazaki, S. Kyo, T. Miyamoto, S. Suzuki, T. Ehara, T. Kakizawa, M. Hara, L. J. DeGroot, et al. Tumor-Specific Gene Therapy for Undifferentiated Thyroid Carcinoma Utilizing the Telomerase Reverse Transcriptase Promoter J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3531 - 3538. [Abstract] [Full Text] [PDF]
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 L. Drucker, O. Uziel, T. Tohami, H. Shapiro, J. Radnay, S. Yarkoni, M. Lahav, and M. Lishner Thalidomide Down-Regulates Transcript Levels of GC-Rich Promoter Genes in Multiple Myeloma Mol. Pharmacol., August 1, 2003; 64(2): 415 - 420. [Abstract] [Full Text] [PDF]
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H. Ma, V. Urquidi, J. Wong, J. Kleeman, and S. Goodison Telomerase Reverse Transcriptase Promoter Regulation During Myogenic Differentiation of Human RD Rhabdomyosarcoma Cells Mol. Cancer Res., August 1, 2003; 1(10): 739 - 746. [Abstract] [Full Text] [PDF]
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N. Ikeda, H. Uemura, H. Ishiguro, M. Hori, M. Hosaka, S. Kyo, K.-i. Miyamoto, E. Takeda, and Y. Kubota Combination Treatment with 1{alpha},25-Dihydroxyvitamin D3 and 9-cis-Retinoic Acid Directly Inhibits Human Telomerase Reverse Transcriptase Transcription in Prostate Cancer Cells Mol. Cancer Ther., August 1, 2003; 2(8): 739 - 746. [Abstract] [Full Text] [PDF]
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T. Veldman, X. Liu, H. Yuan, and R. Schlegel Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter PNAS, July 8, 2003; 100(14): 8211 - 8216. [Abstract] [Full Text] [PDF]
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I. Horikawa and J. C. Barrett Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms Carcinogenesis, July 1, 2003; 24(7): 1167 - 1176. [Abstract] [Full Text] [PDF]
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 X. Fan, Y. Wang, J. Kratz, D. J. Brat, Y. Robitaille, A. Moghrabi, E. J. Perlman, C. V. Dang, P. C. Burger, and C. G. Eberhart hTERT Gene Amplification and Increased mRNA Expression in Central Nervous System Embryonal Tumors Am. J. Pathol., June 1, 2003; 162(6): 1763 - 1769. [Abstract] [Full Text] [PDF]
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S. Wang and J. Zhu Evidence for a Relief of Repression Mechanism for Activation of the Human Telomerase Reverse Transcriptase Promoter J. Biol. Chem., May 23, 2003; 278(21): 18842 - 18850. [Abstract] [Full Text] [PDF]
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 Y.-S. Cong, W. E. Wright, and J. W. Shay Human Telomerase and Its Regulation Microbiol. Mol. Biol. Rev., September 1, 2002; 66(3): 407 - 425. [Abstract] [Full Text] [PDF]
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M. Y. Alfonso-De Matte, H. Yang, M. S. Evans, J. Q. Cheng, and P. A. Kruk Telomerase Is Regulated by c-Jun NH2-Terminal Kinase in Ovarian Surface Epithelial Cells Cancer Res., August 15, 2002; 62(16): 4575 - 4578. [Abstract] [Full Text] [PDF]
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 F. Kumaki, K. Takeda, Z.-X. Yu, J. Moss, and V. J. Ferrans Expression of Human Telomerase Reverse Transcriptase in Lymphangioleiomyomatosis Am. J. Respir. Crit. Care Med., July 15, 2002; 166(2): 187 - 191. [Abstract] [Full Text] [PDF]
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H. Li, T.-H. Lee, and H. Avraham A Novel Tricomplex of BRCA1, Nmi, and c-Myc Inhibits c-Myc-induced Human Telomerase Reverse Transcriptase Gene (hTERT) Promoter Activity in Breast Cancer J. Biol. Chem., May 31, 2002; 277(23): 20965 - 20973. [Abstract] [Full Text] [PDF]
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J.-L. Mergny, J.-F. Riou, P. Mailliet, M.-P. Teulade-Fichou, and E. Gilson Natural and pharmacological regulation of telomerase Nucleic Acids Res., February 15, 2002; 30(4): 839 - 865. [Abstract] [Full Text] [PDF]
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 K. Nomoto, M. Maekawa, K. Sugano, M. Ushiama, N. Fukayama, S. Fujita, and T. Kakizoe Methylation Status and Expression of Human Telomerase Reverse Transcriptase mRNA in Relation to Hypermethylation of the p16 gene in Colorectal Cancers as Analyzed by Bisulfite PCR-SSCP Jpn. J. Clin. Oncol., January 1, 2002; 32(1): 3 - 8. [Abstract] [Full Text] [PDF]
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J. E. Prescott, R. C. Osthus, L. A. Lee, B. C. Lewis, H. Shim, J. F. Barrett, Q. Guo, A. L. Hawkins, C. A. Griffin, and C. V. Dang A Novel c-Myc-responsive Gene, JPO1, Participates in Neoplastic Transformation J. Biol. Chem., December 14, 2001; 276(51): 48276 - 48284. [Abstract] [Full Text] [PDF]
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A.-L. Ducrest, M. Amacker, Y. D. Mathieu, A. P. Cuthbert, D. A. Trott, R. F. Newbold, M. Nabholz, and J. Lingner Regulation of Human Telomerase Activity: Repression by Normal Chromosome 3 Abolishes Nuclear Telomerase Reverse Transcriptase Transcripts but Does Not Affect c-Myc Activity Cancer Res., October 1, 2001; 61(20): 7594 - 7602. [Abstract] [Full Text] [PDF]
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 Y. Yokoyama, X. Wan, Y. Takahashi, A. Shinohara, and T. Tamaya Alternatively spliced variant deleting exons 7 and 8 of the human telomerase reverse transcriptase gene is dominantly expressed in the uterus Mol. Hum. Reprod., September 1, 2001; 7(9): 853 - 857. [Abstract] [Full Text] [PDF]
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L. Gewin and D. A. Galloway E Box-Dependent Activation of Telomerase by Human Papillomavirus Type 16 E6 Does Not Require Induction of c-myc J. Virol., August 1, 2001; 75(15): 7198 - 7201. [Abstract] [Full Text]
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T. Komata, Y. Kondo, T. Kanzawa, S. Hirohata, S. Koga, H. Sumiyoshi, S. M. Srinivasula, B. P. Barna, I. M. Germano, M. Takakura, et al. Treatment of Malignant Glioma Cells with the Transfer of Constitutively Active Caspase-6 Using the Human Telomerase Catalytic Subunit (Human Telomerase Reverse Transcriptase) Gene Promoter Cancer Res., August 1, 2001; 61(15): 5796 - 5802. [Abstract] [Full Text] [PDF]
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M. Takakura, S. Kyo, Y. Sowa, Z. Wang, N. Yatabe, Y. Maida, M. Tanaka, and M. Inoue Telomerase activation by histone deacetylase inhibitor in normal cells Nucleic Acids Res., July 15, 2001; 29(14): 3006 - 3011. [Abstract] [Full Text] [PDF]
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D. L. Crowe, D. C. Nguyen, K. J. Tsang, and S. Kyo E2F-1 represses transcription of the human telomerase reverse transcriptase gene Nucleic Acids Res., July 1, 2001; 29(13): 2789 - 2794. [Abstract] [Full Text] [PDF]
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I. Braunstein, O. Cohen-Barak, C. Shachaf, Y. Ravel, M. Yalon-Hacohen, G. B. Mills, M. Tzukerman, and K. L. Skorecki Human Telomerase Reverse Transcriptase Promoter Regulation in Normal and Malignant Human Ovarian Epithelial Cells Cancer Res., July 1, 2001; 61(14): 5529 - 5536. [Abstract] [Full Text] [PDF]
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F. Pendino, M. Flexor, F. Delhommeau, D. Buet, M. Lanotte, and E. Ségal-Bendirdjian Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation PNAS, May 18, 2001; (2001) 111464998. [Abstract] [Full Text]
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T. Veldman, I. Horikawa, J. C. Barrett, and R. Schlegel Transcriptional Activation of the Telomerase hTERT Gene by Human Papillomavirus Type 16 E6 Oncoprotein J. Virol., May 1, 2001; 75(9): 4467 - 4472. [Abstract] [Full Text]
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D. Xu, N. Popov, M. Hou, Q. Wang, M. Bjorkholm, A. Gruber, A. R. Menkel, and M. Henriksson Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells PNAS, March 27, 2001; 98(7): 3826 - 3831. [Abstract] [Full Text] [PDF]
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 H. Yang, S. Kyo, M. Takatura, and L. Sun Autocrine Transforming Growth Factor {beta} Suppresses Telomerase Activity and Transcription of Human Telomerase Reverse Transcriptase in Human Cancer Cells Cell Growth Differ., February 1, 2001; 12(2): 119 - 127. [Abstract] [Full Text]
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B.-S. Herbert, A. C. Wright, C. M. Passons, W. E. Wright, I. U. Ali, L. Kopelovich, and J. W. Shay Effects of Chemopreventive and Antitelomerase Agents on the Spontaneous Immortalization of Breast Epithelial Cells J Natl Cancer Inst, January 3, 2001; 93(1): 39 - 45. [Abstract] [Full Text] [PDF]
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S. F. Hoare, L. A. Bryce, G. B. A. Wisman, S. Burns, J. J. Going, A. G. J. van der Zee, and W. N. Keith Lack of Telomerase RNA Gene hTERC Expression in Alternative Lengthening of Telomeres Cells Is Associated with Methylation of the hTERC Promoter Cancer Res., January 1, 2001; 61(1): 27 - 32. [Abstract] [Full Text]
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 M. Tzukerman, C. Shachaf, Y. Ravel, I. Braunstein, O. Cohen-Barak, M. Yalon-Hacohen, and K. L. Skorecki Identification of a Novel Transcription Factor Binding Element Involved in the Regulation by Differentiation of the Human Telomerase (hTERT) Promoter Mol. Biol. Cell, December 1, 2000; 11(12): 4381 - 4391. [Abstract] [Full Text]
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A. Zhang, C. Zheng, C. Lindvall, M. Hou, J. Ekedahl, R. Lewensohn, Z. Yan, X. Yang, M. Henriksson, E. Blennow, et al. Frequent Amplification of the Telomerase Reverse Transcriptase Gene in Human Tumors Cancer Res., November 1, 2000; 60(22): 6230 - 6235. [Abstract] [Full Text]
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Z. Wang, S. Kyo, M. Takakura, M. Tanaka, N. Yatabe, Y. Maida, M. Fujiwara, J. Hayakawa, M. Ohmichi, K. Koike, et al. Progesterone Regulates Human Telomerase Reverse Transcriptase Gene Expression via Activation of Mitogen-activated Protein Kinase Signaling Pathway Cancer Res., October 1, 2000; 60(19): 5376 - 5381. [Abstract] [Full Text]
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C. Poremba, C. Scheel, B. Hero, H. Christiansen, K.-L. Schaefer, J.-i. Nakayama, F. Berthold, H. Juergens, W. Boecker, and B. Dockhorn-Dworniczak Telomerase Activity and Telomerase Subunits Gene Expression Patterns in Neuroblastoma: A Molecular and Immunohistochemical Study Establishing Prognostic Tools for Fresh-Frozen and Paraffin-Embedded Tissues J. Clin. Oncol., July 1, 2000; 18(13): 2582 - 2592. [Abstract] [Full Text] [PDF]
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K. Fujimoto, S. Kyo, M. Takakura, T. Kanaya, Y. Kitagawa, H. Itoh, M. Takahashi, and M. Inoue Identification and characterization of negative regulatory elements of the human telomerase catalytic subunit (hTERT) gene promoter: possible role of MZF-2 in transcriptional repression of hTERT Nucleic Acids Res., July 1, 2000; 28(13): 2557 - 2562. [Abstract] [Full Text] [PDF]
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Y. Kitagawa, S. Kyo, M. Takakura, T. Kanaya, K. Koshida, M. Namiki, and M. Inoue Demethylating Reagent 5-Azacytidine Inhibits Telomerase Activity in Human Prostate Cancer Cells through Transcriptional Repression of hTERT Clin. Cancer Res., July 1, 2000; 6(7): 2868 - 2875. [Abstract] [Full Text]
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S. Misiti, S. Nanni, G. Fontemaggi, Y.-S. Cong, J. Wen, H. W. Hirte, G. Piaggio, A. Sacchi, A. Pontecorvi, S. Bacchetti, et al. Induction of hTERT Expression and Telomerase Activity by Estrogens in Human Ovary Epithelium Cells Mol. Cell. Biol., June 1, 2000; 20(11): 3764 - 3771. [Abstract] [Full Text]
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Q. Gao, A. Kumar, S. Srinivasan, L. Singh, H. Mukai, Y. Ono, D. E. Wazer, and V. Band PKN Binds and Phosphorylates Human Papillomavirus E6 Oncoprotein J. Biol. Chem., May 12, 2000; 275(20): 14824 - 14830. [Abstract] [Full Text] [PDF]
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T. Kanaya, S. Kyo, K. Hamada, M. Takakura, Y. Kitagawa, H. Harada, and M. Inoue Adenoviral Expression of p53 Represses Telomerase Activity through Down-Regulation of Human Telomerase Reverse Transcriptase Transcription Clin. Cancer Res., April 1, 2000; 6(4): 1239 - 1247. [Abstract] [Full Text]
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S. Kyo, M. Takakura, T. Taira, T. Kanaya, H. Itoh, M. Yutsudo, H. Ariga, and M. Inoue Sp1 cooperates with c-Myc to activate transcription of the human telomerase reverse transcriptase gene (hTERT) Nucleic Acids Res., February 1, 2000; 28(3): 669 - 677. [Abstract] [Full Text] [PDF]
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S. K. Dessain, H.-y. Yu, R. R. Reddel, R. L. Beijersbergen, and R. A. Weinberg Methylation of the Human Telomerase Gene CpG Island Cancer Res., February 1, 2000; 60(3): 537 - 541. [Abstract] [Full Text]
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S. Oh, Y. Song, J. Yim, and T. K. Kim The Wilms' Tumor 1 Tumor Suppressor Gene Represses Transcription of the Human Telomerase Reverse Transcriptase Gene J. Biol. Chem., December 24, 1999; 274(52): 37473 - 37478. [Abstract] [Full Text] [PDF]
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S. Kyo, M. Takakura, T. Kanaya, W. Zhuo, K. Fujimoto, Y. Nishio, A. Orimo, and M. Inoue Estrogen Activates Telomerase Cancer Res., December 1, 1999; 59(23): 5917 - 5921. [Abstract] [Full Text] [PDF]
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T. R. Devereux, I. Horikawa, C. H. Anna, L. A. Annab, C. A. Afshari, and J. C. Barrett DNA Methylation Analysis of the Promoter Region of the Human Telomerase Reverse Transcriptase (hTERT) Gene Cancer Res., December 1, 1999; 59(24): 6087 - 6090. [Abstract] [Full Text] [PDF]
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J.-P. LIU Studies of the molecular mechanisms in the regulation of telomerase activity FASEB J, December 1, 1999; 13(15): 2091 - 2104. [Abstract] [Full Text]
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K. Nozawa, K. Maehara, and K.-i. Isobe Mechanism for the Reduction of Telomerase Expression during Muscle Cell Differentiation J. Biol. Chem., June 15, 2001; 276(25): 22016 - 22023. [Abstract] [Full Text] [PDF]
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B. Ogretmen, J. M. Kraveka, D. Schady, J. Usta, Y. A. Hannun, and L. M. Obeid Molecular Mechanisms of Ceramide-mediated Telomerase Inhibition in the A549 Human Lung Adenocarcinoma Cell Line J. Biol. Chem., August 24, 2001; 276(35): 32506 - 32514. [Abstract] [Full Text] [PDF]
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J. S. Knight, M. A. Cotter II, and E. S. Robertson The Latency-associated Nuclear Antigen of Kaposi's Sarcoma-associated Herpesvirus Transactivates the Telomerase Reverse Transcriptase Promoter J. Biol. Chem., June 15, 2001; 276(25): 22971 - 22978. [Abstract] [Full Text] [PDF]
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F. Pendino, M. Flexor, F. Delhommeau, D. Buet, M. Lanotte, and E. Segal-Bendirdjian Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation PNAS, June 5, 2001; 98(12): 6662 - 6667. [Abstract] [Full Text] [PDF]
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