Telomerase reverse transcriptase in the regulation of gene expression
Telomerase reverse transcriptase in the regulation of gene expression
BMB Reports. 2014. Jan, 47(1): 8-14
Copyright © 2014, Korean Society for Biochemistry and Molecular Biology
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  • Received : December 16, 2013
  • Published : January 30, 2014
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Junzhi Zhou
Deqiang Ding
Miao Wang
Yu-Sheng Cong

Telomerase plays a pivotal role in the pathology of aging and cancer by maintaining genome integrity, controlling cell proliferation, and regulating tissue homeostasis. Telomerase is essentially composed of an RNA component, Telomerase RNA or TERC , which serves as a template for telomeric DNA synthesis, and a catalytic subunit, telomerase reverse transcriptase (TERT). The canonical function of TERT is the synthesis of telomeric DNA repeats, and the maintenance of telomere length. However, accumulating evidence indicates that TERT may also have some fundamental functions that are independent of its enzymatic activity. Among these telomere-independent activities of hTERT, the role of hTERT in gene transcription has been investigated in detail. Transcriptional regulation is a fundamental process in biological systems. Several studies have shown a direct involvement of hTERT in gene transcription. This mini-review will focus on the role of hTERT in gene transcription regulation, and discuss its possible mechanisms. [BMB Reports 2014; 47(1): 8-14]
Telomeres are located at the ends of eukaryotic chromosomes, and consist of repeat GC sequences that are bound by multiple telomeric proteins, which help guarantee chromosomal integrity (1) . Experimental data from genetically modified mice and human premature aging diseases clearly indicate that intact telomere function is crucial for cell proliferation and survival; whereas, dysfunctional telomeres can lead to either cancer or aging pathologies, depending on the integrity of the cellular stress response pathways. Human telomerase is essentially composed of RNA subunits ( hTR ), together with a reverse transcriptase catalytic subunit (hTERT), whose main function is to maintain telomere length, allowing cells to subvert the Hayflick limit (2) . Telomerase activity is repressed during embryonic differentiation, but remains active in the germ line, and in stem cells and activated lymphocytes. Telomerase is reactivated in 90% of all cancers (3) , suggesting that the activation of telomerase is a critical step in human carcinogenicity. Telomerase has also been linked to aging, and aging-associated pathologies. Dysfunctional telomeres may result in tissue atrophy, deficient tissue regeneration, or stem cell depletion (4) . In humans, loss-of-function mutations in either hTERT or hTR are associated with diseases, such as aplastic anemia, pulmonary fibrosis, and dyskeratosis congenita (5) .
In addition to the role of telomerase in bypassing the replicative senescence of normal human cells, the upregulation of telomerase activity in cancer cells promotes cell proliferation, invasion, and resistance to apoptosis. Increasing evidence indicates that hTERT also has non-telomeric functions that are independent of its conventional function in telomere synthesis. It has been demonstrated that telomerase directly regulates the expression of specific genes belonging to the NF-κB signaling pathway or the Wnt/β-catenin pathway (6 - 9) , participates in DNA damage repair, and promotes cell survival under oxidative stress or endoplasmic reticulum stress conditions (10) . Additionally, it has been shown that hTERT protects developing neurons from DNA damage-induced cell death (11) . TERT also regulates mitochondrial function and cell metabolism (12 - 15) . Among the telomere-independent activities of hTERT, the role of hTERT in gene transcription has been investigated in detail. Several studies have shown a direct involvement of hTERT in gene transcription.
An increasing number of studies have indicated that telomerase has a regulatory role in gene expression. An early study showed that ectopic expression of hTERT in human mammary epithelial cells resulted in the upregulation of five growth promoting genes, and the downregulation of seven growth inhibitory genes (16) . Expression profiling analysis of the human foreskin fibroblasts BJ cells and BJ cells transfected with an hTERT expression construct identified 172 differentially expressed genes, and further demonstrated that epiregulin, a potent growth factor, was highly expressed in the hTERT-BJ cells, and that the inhibition of epiregulin expression triggered a senescence program in the hTERT-BJ cells (17) . It has also been reported that hTERT regulates Mac-2BP, VEGF, and cyclin D1 expression at the transcriptional levels (18 , 19) . Additionally, global expression profiling experiments in bovine adrenocortical cells with ectopically expressed hTERT showed that a total of 284 genes that were associated with cell cycle regulation, metabolism, differentiation and apoptosis were altered by hTERT overexpression (20) .
However, the detailed mechanisms by which telomerase participates in gene expression are largely unknown, and several hypotheses have been proposed. One theory suggests that telomerase may be involved in epigenetic modifications or the modulation of chromatin structure, which indirectly affect gene expression. In support of this hypothesis, it has been observed that overexpression of hTERT upregulated and stabilized DNA 5-methylcytosine transferase I in normal human fibroblasts (21) , and the suppression of hTERT expression altered the overall configuration of chromatin (22) . Another possible mechanism is that telomerase may interact with transcription factors or chromatin modifying factors that directly regulate certain gene transcription programs. In this regard, it has been shown that hTERT interacts with NF-κB p65 and β-catenin, and mediates the transcriptional regulation of target gene expression.
It has been well established that telomerase activation is a prerequisite for tumorigenesis and malignant transformation (23 , 24) . However, the mechanisms by which hTERT is employed in cancer progression remain unclear. It was recently demonstrated that TERT regulates NF-κB-dependent gene transcription, independent of its telomerase enzymatic activity. The NF-κB signaling pathway is a master regulator of cellular and developmental events, and the key transcription factor p65/p50 dimer regulates the expression of a large number of genes, in response to physiological and pathological stimuli and stress, which play important roles in the canonical activation of the NF-κB signaling pathway (10 , 25 , 26) . Both TERT and NF-κB are activated in cancerous cells. Studies have suggested that NF-κB activates the expression of TERT, by binding to the promoter of TERT (27) , and p65 was shown to modulate hTERT translocation from the cytoplasm to the nucleus in MM.1S cells, and promote the expression of hTERT in HepG2 cells (28 , 29) . These results indicated that hyperactivation of NF-κB could promote tumorigenesis, by activating the expression of TERT. However, Ghosh et al. recently suggested that hTERT directly regulates the expression of the NF-κB-dependent genes by binding to p65, and localizing to a subset of NF-κB promoters, such as IL-6, TNF-α and IL-8 . They observed that si-TERT had a more pronounced effect on the expression of TNF-α and IL-6 , compared to MCP1 and IκBα . They further found that TERT selectively occupied the IL-6, TNF-α and IL-8 promoters; however, TERT binding to the MCP1 promoter was weak, and binding was almost absent at the IκBα promoter.
Chip sequencing analysis indicated that TERT is required for optimal p65 binding to a small proportion of NF-κB dependent target genes, following TNF-α stimulation. It appears that the TERT-mediated gene expression is dependent on the context of the NF-κB binding site in the promoter. They further found that, in addition to the NF-κB binding site, there was a T 2 G 3 sequence within the IL6A, IL8A and TNF-α promoters that may function as a putative hTERT binding site (30) . These results indicate that TERT-mediated NF-κB dependent gene transcription may rely on the presence of the T 2 G 3 sequence near the NF-κB binding site in their promoters. However, this hypothesis needs more experimental support. Importantly, we recently showed that TERT regulates MMP family gene expression via NF-κB-dependent transcription, in a manner independent of its telomerase activity. We observed that both TERT and TERT K626A regulated the expression of NF-κB target genes, such as IL-6, IL-8, MMP1 and IκBα , in U2OS and HeLa cells (7) . Given that both telomerase and NF-κB are hyperactivated in an equally large number of cancers, the functional interaction of telomerase and NF-κB might be a key missing molecular link that mediates the effects of reactivated telomerase in cancer cells. These data could explain the upregulation of inflammation-related gene expression in patients with metabolic syndromes (31) , and the regulation of immune cell functions by telomerase activity (32) . Taken together, these findings indicated that the feed-forward loop between NF-κB and telomerase not only drives multiple hallmarks of cancer, but also is an early event that promotes cancer progression.
Additionally, we previously reported that hTERT could activate the transcription of vascular endothelial growth factor (VEGF), independent of telomerase activity in HeLa cells (33) . However, we performed a mammalian one-hybrid assay in multiple cell lines, and we found that hTERT has no direct transcriptional activity. The mechanism by which TERT regulates VEGF may be mediated by its interaction with other transcription factors, such as p65 and Sp1. Liu et al. suggested that TERT promotes the transcription of epithelial mesenchymal transition (EMT)-related genes, such as vimentin and snail1 , independent of telomerase activity in gastric cancer (34) . They further found that hTERT interacted with β-catenin, and occupied the promoters of β-catenin target genes, such as vimentin . Given that the MMP family, EMT, and angiogenesis-related genes, such as VEGF , are important for cell invasion, transformation, and angiogenesis, respectively, these studies may thus explain how hTERT also exhibits non-telomeric functions in tumor progression.
Canonical Wnt/β-catenin signaling regulates many biological processes, including cell fate decision, axis formation and organ development, and mutations in the Wnt pathway resulting in tumorigenesis (35) . The Wnt signaling pathway is composed of extracellular protein ligands, receptors on the cell membrane, the cell signal transduction system in the cytoplasm, and gene transcription regulation elements within the nucleus. The transcriptional activator β-catenin is a key effector of this pathway. When Wnt signaling is turned off, the tumor suppressor adenomatous polyposis coli (APC), Axin, and β-catenin form protein complexes in the cytoplasm, leading to the phosphorylation of β-catenin by CKI and GSK3β, and its degradation by the 26S proteasome. When Wnt signaling is turned on, the APC-Axin-GSK3β complex is destabilized through Dsh, and β-catenin is no longer degraded, leading to its accumulation in the cytoplasm. Stabilized β-catenin enters the nucleus, and activates the transcription of downstream target genes, in concert with the TCF/LEF family of transcription factors (36) . The Wnt pathway regulates the self-renewal of stem cells and/or progenitor cells in a variety of tissues and organs, and dysfunction of the Wnt pathway has been implicated in a number of cancers (37) . Telomerase activity is repressed during embryonic differentiation, but remains active in the germ line. The Wnt pathway and telomerase have both been implicated in embryonic development and tissue homeostasis, suggesting that they have a functional link and/or regulation. Studies showed that TERT can directly promote the cell cycle entry of quiescent epidermal stem cells (38 , 39) , suggesting that TERT has its own activity in the stem cell, independent of its telomerase activity. However, the mechanism by which TERT regulates stem cell behavior is not understood.
In 2008, Artandi’s group first studied the link between the Wnt pathway and TERT. They investigated the genome-wide transcriptional response to acute changes in TERT or TERT ci (TERT mutant lacking RT function) expression in mammalian skin, an ideal tissue for progenitor cell biology research. They observed that TERT induced the anagen phase of the hair cycle, promoted hair growth, activated hair follicle stem cells, and caused hyperproliferation in the basal layer of interfollicular skin, independent of telomerase activity. They further discovered that acute withdrawal of TERT resulted in a substantial change in the expression of genes related to epithelial development, adhesion and signaling transduction. Gene Set Enrichment Analysis (GSEA) revealed a significant correlation between TERT, and two pathways, Wnt and Myc. Activated TERT upregulated Wnt, Shh and BMP pathway related genes, such as Bambi, Bmp8a, Ccnd2, Lef1, Nkd2, Smad, Wnt5a and Wnt11 . MSigDB (a database detailing which genes harbor conserved elements for each specific regulatory motif) analysis further suggested that E-boxes, which are recognized by Myc/Max heterodimers, and TCF/TEF binding sites, which bind β-catenin, were significantly enriched in the TERT-activated and TERT-repressed genes (9) . Artandi’s group further revealed a novel role of telomerase in the regulation of the Wnt/β-catenin signaling pathway. TERT acts as a cofactor in the β-catenin transcription complex; in this complex, TERT interacts with BRG1, a chromatin remodeling factor, to regulate the Wnt/β-catenin signaling pathway (8) . It has been reported that TERT, BRG1 and NS/GNL3L (GTP-binding protein nucleostemin) form a complex that regulates the cancer cell state (40) . Overexpression of TERT in normal human fibroblasts activated the expression of DNMT1 (DNA methyltransferase I), through the STAT3 transcription factor (41) . Studies showed that EGFR acts as a transducer of the signal between TERT and STAT3 (42) . Because elevated levels of NS/GNL3L increased the phosphorylation of STAT3 (40) , it is possible that TERT indirectly regulates STAT3 through NS/GNL3L. Additionally, Xu’s lab found that TERT indirectly interacts with β-catenin, and occupies the promoters of β-catenin target genes, to promote the epithelial mesenchymal transition in cancer cells (34) . However, Liu et al. failed to observe a physical interaction between hTERT and BRG1 in human cells. They demonstrated that hTERT could directly interact with β-catenin, and prevent its nuclear retention and degradation (34) . Additionally, Greider’s lab suggested that there were indistinguishable phenotypes between the mice deficient in mTERT and mTR, and no apparent Wnt pathway defects were observed in the mTERT -/- mice (43) . Ghosh et al. failed to verify the physical association of hTERT and BRG1, following stimulation with TNF-α (30) .
Recently, Blackburn’s lab investigated the effects of TERT on the Wnt pathway in MCF7 and HeLa cells (44) . They failed to verify the physical association of hTERT and BRG1 or β-catenin. One possible explanation for this discrepancy may be that two mechanisms are employed by hTERT and mTERT, respectively, to regulate the Wnt/β-catenin pathway (34) . Many studies showing a role for TERT in the regulation of gene expression have been based on the upregulation or downregulation of TERT in a transient fashion. However, whether the telomere-independent functions of TERT on gene regulation, or the Wnt signaling pathway, are physiologically relevant, remain to be seen. It is possible that the impact of TERT on the regulation of the Wnt/β-catenin signaling pathway may become biologically relevant, under particular physiopathological conditions (45) . It has been found that TERT not only activated the Wnt/β-catenin pathway, but β-catenin could also directly regulate the transcription of TERT, by interacting with KLF4 in the NTera2 and SW480 carcinoma cell lines (46) . Together, these studies suggest that hTERT could influence stem cell functions in two ways: TERT could activate the transcription of β-catenin-dependent genes, or Wnt/β-catenin could regulate the transcription of TERT, which results in telomere maintenance.
Many reports have shown that TERT plays a direct role in the regulation of gene expression. Recently, Maida et al. suggested that TERT may regulate gene expression in a telomere-independent manner at the posttranscription level (47) . It has been suggested that hTERT could interact with the RNA component of the mitochondrial RNA-processing endoribonuclease (RMRP), to form a ribonucleoprotein complex that has RNA-dependent RNA polymerase activity. Using RMRP as a template, the TERT-RMRP complex could produce dsRNAs, which are processed into 22 nucleotide siRNAs that specifically silence the expression of RMRP, in a Dicer-dependent manner. RMRP is a 267 nucleotide non-coding RNA that is highly expressed in many human and murine tissues. RMRP mutations are associated with Cartilage Hair Hypoplasia (CHH) (48 , 49) . Rosenbluh et al. were unable to obtain viable homozygous RMRP null mice, and they claimed that RMRP is essential for early embryonic development (50) . It has also been suggested that RMRP RNA binds to the mitochondria, and modifies the RNase MRP complex at posttranscriptional level (49) . Recently, Sharma et al. suggested the mitochondrial hTERT could bind different mitochondrial RNAs, and acts in a telomere-independent manner (51) . It is possible that there are RNAs other than RMRP that associate with TERT, to regulate gene expression in the mitochondria. A growing body of research suggests that TERT has important effects on mitochondrial function in a telomere-independent manner (14 , 52 - 55) ; however, the mechanism by which TERT protects mitochondrial function is not completely understood. Whether TERT-RMRP or TERT-RNAs (non-RMRP) are required for mitochondrial function under physiological or pathological conditions remains to be elucidated.
Kashani-Sabet’s group showed that stable suppression of mTERC in the murine melanoma B16 cell line resulted in the significant downregulation of 138 genes, 8 of which are involved in the glycolytic pathway. Interestingly, changes in the expression of glycolytic enzymes indicated a functional link between telomerase and cancer metabolism (56) . Cancer cells frequently experience endoplasmic reticulum stress, such as glucose deprivation conditions; therefore, the association of hTERT expression with the glycolytic pathway may contribute to the resistance of cancer cells to regulation by the tumor microenvironment. Blackburn’s group demonstrated that targeting hTR in the human colon cancer HCT116 cell line resulted in the suppression of specific genes that have been implicated in angiogenesis and metastasis (57) . It seems that the telomerase template RNA ( TERC ) can also participate in the telomerase-mediated NF-κB transcription. The expression of some NF-κB target genes is decreased in the TERC knockout mice, similar to the TERT knockout mice (30) . The concrete mechanism by which telomerase participates in the regulation of NF-κB target genes requires further investigation.
The main function of TERT is to maintain the telomere. However, accumulating evidence indicates that TERT may also have some functions that are independent of its telomerase activity. A number of studies suggest that telomerase plays a role in the regulation of gene expression in a telomere-independent manner ( Fig. 1 ). Telomerase/TERT may act as a transcription modulator through its interaction with transcription factors, such as p65, β-catenin or BRG1; and may regulate certain gene transcription programs, as described for the NF-κB signaling pathway, and the Wnt/β-catenin pathway. TERT may be able to form different complexes in different cell contexts, to participate in the regulation of gene expression in certain pathways. Additionally, the function of TERC in the regulation of gene expression is not clear. It appears that TERT can form complexes with or without TERC . It will be interesting to learn whether TERC is required for the TERT-mediated gene transcription regulation. However, changes in telomerase/TERT levels, in response to certain physiological or pathological conditions, may also regulate telomere length or state in a transient fashion, which subsequently affect the telomeric or sub-telomeric chromatin, and in turn, can regulate gene transcription. Whether telomerase/TERT directly participates in gene transcription is currently under debate, and results from the different research groups are controversial. Future work should include detailed biochemical studies and model systems to confirm the existing data, and to understand the biological significance.
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hTERT in regulation of gene expression.
This work was supported by grants from the National Basic Research Program of China (2012CB911203), and the National Natural Science Foundation of China (31371398, 31171320, 31071200).
Blackburn E. H , Greider C. W , Henderson E , Lee M. S. , Shampay J. , Shippen-Lentz D. (1989) Recognition and elongation of telomeres by telomerase. Genome 31 553 - 560    DOI : 10.1139/g89-104
Verdun R. E. , Karlseder J. (2007) Replication and protection of telomeres. Nature 447 924 - 931    DOI : 10.1038/nature05976
Harley C. B. (2008) Telomerase and cancer therapeutics. Nat. Rev. Cancer 8 167 - 179    DOI : 10.1038/nrc2275
Jaskelioff M. , Muller F. L. , Paik J. H. , Thomas E. , Jiang S. , Adams A. C. , Sahin E. , Kost-Alimova M. , Protopopov A. , Cadinanos J. , Horner J. W. , Maratos-Flier E. , Depinho R. A. (2011) Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 469 102 - 106    DOI : 10.1038/nature09603
Dokal I. (2011) Dyskeratosis congenita. Hematology Am. Soc. Hematol. Educ. Program 2011 480 - 486    DOI : 10.1182/asheducation-2011.1.480
Ghosh A. , Saginc G. , Leow S. C. , Khattar E. , Shin E. M. , Yan T. D. , Wong M. , Zhang Z. Z. , Li G. L. , Sung W. K. , Zhou J. B. , Chng W. J. , Li S. , Liu E. , Tergaonkar V. (2012) Telomerase directly regulates NF-kappa B-dependent transcription. Nat. Cell Biol. 14 1270 - 1281    DOI : 10.1038/ncb2621
Ding D. , Xi P. , Zhou J. , Wang M. , Cong Y. S. (2013) Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NFkappaB-dependent transcription. FASEB J. 27 4375 - 4383    DOI : 10.1096/fj.13-230904
Park J. I. , Venteicher A. S. , Hong J. Y. , Choi J. , Jun S. , Shkreli M. , Chang W. , Meng Z. , Cheung P. , Ji H. , McLaughlin M. , Veenstra T. D. , Nusse R. , McCrea P. D. , Artandi S. E. (2009) Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460 66 - 72    DOI : 10.1038/nature08137
Choi J. K. , Southworth L. K. , Sarin K. Y. , Venteicher A. S. , Ma W. X. , Chang W. , Cheung P. , Jun S. H. , Artandi M. K. , Shah N. , Kim S. K. , Artandi S. E. (2008) TERT promotes epithelial proliferation through transcriptional control of a Myc- and Wnt-related developmental program. Plos. Genet 4 0124 - 0138    DOI : 10.1371/journal.pgen.0040010
Zhou J. , Mao B. , Zhou Q. , Ding D. , Wang M. , Guo P. , Gao Y. , Shay J. W. , Yuan Z. , Cong Y. S. (2013) Endoplasmic reticulum stress activates telomerase. Aging Cell    DOI : 10.1111/acel.12161.
Fu W. , Killen M. , Culmsee C. , Dhar S. , Pandita T. K. , Mattson M. P. (2000) The catalytic subunit of telomerase is expressed in developing brain neurons and serves a cell survival-promoting function. J. Mol. Neurosci. 14 3 - 15    DOI : 10.1385/JMN:14:1-2:003
Haendeler J. , Drose S. , Buchner N. , Jakob S. , Altschmied J. , Goy C. , Spyridopoulos I. , Zeiher A. M. , Brandt U. , Dimmeler S. (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler. Thromb. Vasc. Biol. 29 929 - 935    DOI : 10.1161/ATVBAHA.109.185546
Indran I. R. , Hande M. P. , Pervaiz S. (2011) hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res. 71 266 - 276    DOI : 10.1158/0008-5472.CAN-10-1588
Kovalenko O. A. , Caron M. J. , Ulema P. , Medrano C. , Thomas A. P. , Kimura M. , Bonini M. G. , Herbig U. , Santos J. H. (2010) A mutant telomerase defective in nuclear-cytoplasmic shuttling fails to immortalize cells and is associated with mitochondrial dysfunction. Aging Cell 9 203 - 219    DOI : 10.1111/j.1474-9726.2010.00551.x
Cong Y. , Shay J. W. (2008) Actions of human telomerase beyond telomeres. Cell Res 18 725 - 732    DOI : 10.1038/cr.2008.74
Smith L. L. , Coller H. A. , Roberts J. M. (2003) Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat. Cell Biol. 5 474 - 479    DOI : 10.1038/ncb985
Lindvall C. , Hou M. , Komurasaki T. , Zheng C. , Henriksson M. , Sedivy J. M. , Bjorkholm M , Teh B. T. , Nordenskjold M. , Xu D. (2003) Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by gene expression profiling: activation of the epiregulin gene. Cancer Res. 63 1743 - 1747
Park Y. P. , Choi S. C. , Kim J. H. , Song E. Y. , Kim J. W. , Yoon D. Y. , Yeom Y. I. , Lim J. S. , Paik S. G. , Lee H. G. (2007) Up-regulation of Mac-2 binding protein by hTERT in gastric cancer. Int. J. Cancer 120 813 - 820    DOI : 10.1002/ijc.22369
Jagadeesh S. , Banerjee P. P. (2006) Telomerase reverse transcriptase regulates the expression of a key cell cycle regulator, cyclin D1. Biochem. Biophys. Res. Commun. 347 774 - 780    DOI : 10.1016/j.bbrc.2006.06.172
Perrault S. D. , Hornsby P. J. , Betts D. H. (2005) Global gene expression response to telomerase in bovine adrenocortical cells. Biochem. Biophys. Res. Commun. 335 925 - 936    DOI : 10.1016/j.bbrc.2005.07.156
Young J. I. , Sedivy J. M. , Smith J. R. (2003) Telomerase expression in normal human fibroblasts stabilizes DNA 5-methylcytosine transferase I. J. Biol. Chem. 278 19904 - 19908    DOI : 10.1074/jbc.M301685200
Masutomi K. , Possemato R. , Wong J. M. , Currier J. L. , Tothova Z. , Manola J. B. , Ganesan S. , Lansdorp P. M. , Collins K. , Hahn W. C. (2005) The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl. Acad. Sci. U. S. A. 102 8222 - 8227    DOI : 10.1073/pnas.0503095102
Hanahan D. , Weinberg R. A. (2000) The hallmarks of cancer. Cell 100 57 - 70    DOI : 10.1016/S0092-8674(00)81683-9
Stewart S. A. , Hahn W. C. , O&Connor B. F. , Banner E. N. , Lundberg A. S. , Modha P. , Mizuno H. , Brooks M. W. , Fleming M. , Zimonjic D. B , Popescu N. C. , Weinberg R. A. (2002) Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl. Acad. Sci. U. S. A. 99 12606 - 12611    DOI : 10.1073/pnas.182407599
Perkins N. D. (2012) The diverse and complex roles of NF-kappaB subunits in cancer. Nat. Rev. Cancer 12 121 - 132
Oeckinghaus A. , Hayden M. S. , Ghosh S. (2011) Crosstalk in NF-kappaB signaling pathways. Nat. Immunol. 12 695 - 708    DOI : 10.1038/ni.2065
Yin L. , Hubbard A. K. , Giardina C. (2000) NF-kappa B regulates transcription of the mouse telomerase catalytic subunit. J. Biol. Chem. 275 36671 - 36675    DOI : 10.1074/jbc.M007378200
Akiyama M. , Hideshima T. , Hayashi T. , Tai Y. T. , Mitsiades C. S. , Mitsiades N. , Chauhan D. , Richardson P. , Munshi N. C. , Anderson K. C. (2002) Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res. 62 3876 - 3882
Zuo Q. P. , Liu S. K. , Li Z. J. , Li B. , Zhou Y. L. , Guo R. , Huang L. H. (2011) NF-kappaB p65 modulates the telomerase reverse transcriptase in the HepG(2) hepatoma cell line. Eur. J.Pharmacol. 672 113 - 120    DOI : 10.1016/j.ejphar.2011.09.187
Ghosh A. , Saginc G. , Leow S. C. , Khattar E. , Shin E. M. , Yan T. D. , Wong M. , Zhang Z. , Li G. , Sung W. K. , Zhou J. , Chng W. J , Li S. , Liu E. , Tergaonkar V. (2012) Telomerase directly regulates NF-kappaB-dependent transcription. Nat. Cell Biol. 14 1270 - 1281    DOI : 10.1038/ncb2621
Rentoukas E. , Tsarouhas K. , Kaplanis I. , Korou E. , Nikolaou M. , Marathonitis G. , Kokkinou S. , Haliassos A. , Mamalaki A. , Kouretas D. , Tsitsimpikou C. (2012) Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS One. 7 e35739 -    DOI : 10.1371/journal.pone.0035739
Gizard F. , Heywood E. B. , Findeisen H. M. , Zhao Y. , Jones K. L. , Cudejko C. , Post G. R. , Staels B. , Bruemmer D. (2011) Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler. Thromb. Vasc. Biol. 31 245 - 252    DOI : 10.1161/ATVBAHA.110.219808
Zhou L. , Zheng D. , Wang M. , Cong Y. S. (2009) Telomerase reverse transcriptase activates the expression of vascular endothelial growth factor independent of telomerase activity. Biochem. Biophys. Res. Commun. 386 739 - 743    DOI : 10.1016/j.bbrc.2009.06.116
Liu Z. , Li Q. , Li K. , Chen L. , Li W. , Hou M. , Liu T. , Yang J. , Lindvall C. , Bjorkholm M. , Jia J. , Xu D. (2013) Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells. Oncogene 32 4203 - 4213    DOI : 10.1038/onc.2012.441
Anastas J. N. , Moon R. T. (2013) WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13 11 - 26    DOI : 10.1038/nrc3419
Behrens J. , von Kries J. P. , Kuhl M , Bruhn L., , Wedlich D , Grosschedl R. , Birchmeier W. (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382 638 - 642    DOI : 10.1038/382638a0
Clevers H. (2006) Wnt/beta-catenin signaling in development and disease. Cell 127 469 - 480    DOI : 10.1016/j.cell.2006.10.018
Sarin K. Y. , Cheung P. , Gilison D. , Lee E. , Tennen R. I. , Wang E. , Artandi M. K. , Oro A. E. , Artandi S. E. (2005) Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436 1048 - 1052    DOI : 10.1038/nature03836
Flores I. , Cayuela M. L. , Blasco M. A. (2005) Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309 1253 - 1256    DOI : 10.1126/science.1115025
Okamoto N. , Yasukawa M. , Nguyen C. , Kasim V. , Maida Y. , Possemato R. , Shibata T. , Ligon L. , Fukami K. , Hahn W. C. , Masutomi K. (2011) Maintenance of tumor initiating cells of defined genetic composition by nucleostemin. Proc. Natl. Acad. Sci. U. S. A. 108 20388 - 20393    DOI : 10.1073/pnas.1015171108
Zhang Q. , Wang H. Y. , Woetmann A. , Raghunath P. N. , Odum N. , Wasik M. A. (2006) STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. Blood 108 1058 - 1064    DOI : 10.1182/blood-2005-08-007377
Park O. K , Schaefer T. S. , Nathans D. (1996) In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc. Natl. Acad. Sci. U. S. A. 93 13704 - 13708    DOI : 10.1073/pnas.93.24.13704
Strong M. A. , Vidal-Cardenas S. L. , Karim B. , Yu H. , Guo N. , Greider C. W. (2011) Phenotypes in mTERT(+)/(-) and mTERT(-)/(-) mice are due to short telomeres, not telomere-independent functions of telomerase reverse transcriptase. Mol. Cell. Biol. 31 2369 - 2379    DOI : 10.1128/MCB.05312-11
Listerman I. , Gazzaniga F. S. , Blackburn E. H. (2013) An investigation of the effects of the telomerase core protein TERT on Wnt signaling in human breast cancer cells. Mol. Cell. Biol.    DOI : 10.1128/MCB.00844-13
Ding D. , Zhou J. , Wang M. , Cong Y. S. (2013) Implications of telomere-independent activities of telomerase reverse transcriptase in human cancer. FEBS. J. 280 3205 - 3211    DOI : 10.1111/febs.12258
Hoffmeyer K. , Raggioli A. , Rudloff S. , Anton R. , Hierholzer A. , Del Valle I. , Hein K. , Vogt R. , Kemler R. (2012) Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science 336 1549 - 1554    DOI : 10.1126/science.1218370
Maida Y , Yasukawa M , Furuuchi M , Lassmann T , Possemato R , Okamoto N , Kasim V , Hayashizaki Y , Hahn W. C. , Masutomi K. (2009) An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461 230 - 235    DOI : 10.1038/nature08283
Ridanpaa M. , van Eenennaam H. , Pelin K. , Chadwick R. , Johnson C. , Yuan B. , vanVenrooij W. , Pruijn G. , Salmela R. , Rockas S. , Makitie O. , Kaitila I. , de la Chapelle A. (2001) Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell 104 195 - 203    DOI : 10.1016/S0092-8674(01)00205-7
Chang D. D. , Clayton D. A. (1987) A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA. Science 235 1178 - 1184    DOI : 10.1126/science.2434997
Rosenbluh J. , Nijhawan D. , Chen Z. , Wong K. K. , Masutomi K. , Hahn W. C. (2011) RMRP is a non-coding RNA essential for early murine development. PLoS One 6 e26270 -    DOI : 10.1371/journal.pone.0026270
Sharma N. K. , Reyes A. , Green P. , Caron M. J. , Bonini M. G , Gordon D. M. , Holt I. J. , Santos J. H. (2012) Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res. 40 712 - 725    DOI : 10.1093/nar/gkr758
Haendeler J. , Drose S. , Buchner N. , Jakob S. , Altschmied J. , Goy C. , Spyridopoulos I. , Zeiher A. M. , Brandt U. , Dimmeler S. (2009) Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler. Thromb. Vasc. Biol. 29 929 - 935    DOI : 10.1161/ATVBAHA.109.185546
Indran I. R. , Hande M. P. , Pervaiz S. (2011) hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res. 71 266 - 276    DOI : 10.1158/0008-5472.CAN-10-1588
Massard C. , Zermati Y. , Pauleau A. L. , Larochette N. , Metivier D. , Sabatier L. , Kroemer G. , Soria J. C. (2006) hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene 25 4505 - 4514    DOI : 10.1038/sj.onc.1209487
Indran I. R. , Hande M. P. , Pervaiz S. (2010) Tumor cell redox state and mitochondria at the center of the non-canonical activity of telomerase reverse transcriptase. Mol. Aspects. Med. 31 21 - 28    DOI : 10.1016/j.mam.2009.12.001
Bagheri S. , Nosrati M. , Li S. , Fong S. , Torabian S. , Rangel J. , Moore D. H. , Federman S. , Laposa R. R. , Baehner F. L. , Sagebiel R. W. , Cleaver J. E. , Haqq C. , Debs R. J. , Blackburn E. H. , Kashani-Sabet M. (2006) Genes and pathways downstream of telomerase in melanoma metastasis. Proc. Natl. Acad. Sci. U. S. A. 103 11306 - 11311    DOI : 10.1073/pnas.0510085103
Li S. , Crothers J. , Haqq C. M. , Blackburn E. H. (2005) Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. J. Biol. Chem. 280 23709 - 23717    DOI : 10.1074/jbc.M502782200