Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity
            <i>via</i>
            NF‐κB‐dependent transcription

Ding, Deqiang; Peng, Xi; Zhou, Junzhi; Wang, Miao; Cong, Yu‐Sheng

doi:10.1096/fj.13-230904

Cited by 117 publications

(116 citation statements)

References 37 publications

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“…Ectopic expression of TERT and its catalytic mutant TERT K626A induced cancer cell invasion, MMP 9 mRNA expression and promoter activity in an NF-κB-dependent manner, regulating several target genes of this signalling pathway (Ding et al 2013).…”

Section: Role Of Tert In Proliferation Invasion and Tumourigenesismentioning

confidence: 98%

“…Reduction of mtDNA damage Improvement of mitochondrial function Higher protection from apoptosis Prevention of nuclear DNA damage (Ahmed et al 2008) (Haendeler et al 2009) (Singhapol et al 2013) Cell death Nuclear TERT localization Diminished mtDNA damage Increase cell survival Protection against cellular senescence (Santos et al 2004) (Santos et al 2006) Nuclear TERT localization High DNA damage (Singhapol et al 2013) (Ding et al 2013) (Hu et al 2015) (Park et al 2007) ) ) ) ) (Liu et al 2013c) (Canela et al 2004) Invasion and metastisation TERT pathway selectively induces TERT mRNA expression in −146C > T mutant cells, in which the mutation creates a binding site specific for p52 that interacts with ETS factors ETS1/2 to mediate TERT reactivation (Li et al 2015b). This study also reports that there is an enhanced tumorigenic and proliferative effect due to NF-κB activation by the increase of telomerase activity dependent on the existence of −146C > T mutation (Li et al 2015b).…”

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

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TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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Evasion of replicative senescence and proliferation without restriction, sometimes designated as immortalisation, is one of the hallmarks of cancer that may be attained through reactivation of telomerase in somatic cells. In contrast to most normal cells in which there is lack of telomerase activity, upregulation of TERT transcription/activity is detected in 80-90% of malignant tumours. In several types of cancer, there is a relationship between the presence of TERT promoter mutations, TERT mRNA expression and clinicopathological features, but the biological bridge between the occurrence of TERT promoter mutations and the aggressive/invasive features displayed by the tumours remains unidentified. We and others have associated the presence of TERT promoter mutations with metastisation/survival in several types of cancer. In follicular cell-derived thyroid cancer, such mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage) as well as with distant metastases, worse response to treatment and poorer survival. In this review, we analyse the data reported in several studies that imply TERT transcription reactivation/activity with cell proliferation, tumour invasion and metastisation. A particular attention is given to the putative connections between TERT transcriptional reactivation and signalling pathways frequently altered in cancer, such as c-MYC, NF-κB and B-Catenin.

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Section: Role Of Tert In Proliferation Invasion and Tumourigenesismentioning

confidence: 98%

Section: Functional Effects Of Tert Promoter Mutations In Tumours Andmentioning

confidence: 99%

TERT biology and function in cancer: beyond immortalisation

Pestana

Vinagre

Sobrinho-Simões

et al. 2017

Journal of Molecular Endocrinology

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“…In particular, the authors demonstrated that both hTERT and its catalytic mutant hTERT K626A, which lacks reverse transcriptase activity, could activate NF-kBmediated transcription and regulate the expression of several NF-kB target genes to similar extents (26). Furthermore, overexpression of hTERT or hTERT K626A promoted the nuclear accumulation of NF-kB p65 as well as p65 DNA binding at both basal and TNF-a-induced states (26). These data reiterate the notion that telomerase can function as a transcriptional modulator of the NF-kB signaling cascade in a fashion distinct from its activity at telomeres.…”

Section: Noncanonical Functions Of Telomerase That Intersect With Sigmentioning

confidence: 99%

Noncanonical Functions of Telomerase: Implications in Telomerase-Targeted Cancer Therapies

2014

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Telomerase plays a pivotal role in bypassing cellular senescence and maintaining telomere homeostasis, essential properties required for the sustenance and progression of cancer. However, recent investigations have uncovered extratelomeric properties of telomerase that are independent of its role in telomere extension. This review summarizes recent insights to the noncanonical functions of telomerase reverse transcriptase (TERT) catalytic subunit, in particular in cancer progression, and highlights two major signaling mechanisms involved in the cross-talk with TERT-the NF-kB and Wnt/b-catenin pathways. We propose a feed-forward regulatory loop mechanism underlying TERT activation in cancers in which TERT acts as a transcriptional modulator of oncogenic signaling pathways that sustain its own levels and control the induction of target genes critical for tumor cell survival and proliferation. Finally, we provide a new perspective on telomerase-targeted cancer therapies and suggest possible interventions targeting the nontelomeric roles of TERT. This therapeutic strategy can be used in the future targeting of other telomerase components that exhibit novel nontelomeric functions in cancer and other ailments. Cancer Res; 74(6);

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“…NF-κB p65 modulates hTERT expression and nuclear translocation from cytoplasm in tumor cells (32,33), and hTERT has been shown to contribute to cancer development and progression as a transcriptional modulator of the NF-κB signaling pathway in a manner independent of telomerase activity (7,8). In the present study, we speculated that the C197 interrupts the forward feedback between hTERT and NF-κB signaling pathway which contributes to the antitumor effect of C197.…”

Section: Discussionmentioning

confidence: 73%

“…However, telomerase is reactivated in vast majority of human cancer cells (5) and plays a critical role in the progression of human cancer (6). Recently telomerase has been found to exert extra-telomeric effects via the modulation of NF-κB (7,8) and Wnt/β-catenin signaling pathways (9,10). These non-canonical functions are associated with the development and progression of human cancer.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effect of COOH-terminal polypeptide of human TERT is associated with the declined expression of hTERT and NF-κBï¿½p65 in HeLaï¿½cells

Chen

Xie

et al. 2015

Oncol Rep

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Abstract. Human telomerase reverse transcriptase (hTERT) plays an important role in the development of tumors and has been investigated as a potent target for anticancer therapy. In the present study, we constructed a recombinant adenovirus, Ad-EGFP-C197 which was capable of expressing COOH-terminal polypeptide of hTERT (amino acid 936-1,132, termed as C197 for the reason that it contains 197 amino acids). Infection of HeLa cells with Ad-EGFP-C197 suppressed the activity of telomerase, decreased the expression of hTERT and NF-κB p65, and induced rapid growth delay and apoptosis of HeLa cells in vitro. In nude mice xenografted with HeLa tumors, injection of Ad-EGFP-C197 into the tumor nodule significantly slowed tumor growth and promoted tumor cell apoptosis, as well as reduced the expression of NF-κB p65 in tumor tissues. In the present study, we suggest that the antitumor effect of C197 is associated with the declined expression of hTERT and NF-κB p65. Our results highlight the potential of C197 in tumor therapy. IntroductionTelomeres are the ends of linear chromosomes in eukaryotic cells and are characterized by the TTAGGG repeats (1) that are bound by the shelterin complex (2). Telomeric DNA shrinks with each cellular division due to incomplete replication of TTAGGG repeats, which eventually results in DNA damage and replicative senescence (3). Telomerase is a particular ribonucleoprotein complex which specifically adds TTAGGG repeats to the ends of eukaryotic chromosomes, thus counteracts the shortening of telomeric DNA during cell division. The activity of telomerase is not detected in most human somatic cells (4). However, telomerase is reactivated in vast majority of human cancer cells (5) and plays a critical role in the progression of human cancer (6). Recently telomerase has been found to exert extra-telomeric effects via the modulation of NF-κB (7,8) and Wnt/β-catenin signaling pathways (9,10). These non-canonical functions are associated with the development and progression of human cancer. In fact, telomerase has been investigated as a potent target for anticancer therapy (11).The major components of human telomerase are tolemerase RNA (hTR) and telomerase reverse transcriptase (hTERT). While hTR subunit serves as a template, hTERT subunit catalyzes the elongation of telomeric DNA. Three main structural domains of hTERT have been identified: NH 2 terminus that binds DNA and RNA, central catalytic RT region and a short COOH terminus (12). Although the function of COOH terminus is the least-characterized, it has been found to mediate the nuclear translocation of telomerase (13) and is essential for the in vivo activity of human telomerase (14). Recent studies showed that ectopic expression of C27 (amino acid 882-1,132 of hTERT) reduces the growth and tumorigenicity of tumor cells (15-19) and sensitizes tumor cells to 5-fluorouracil-induced growth inhibition and apoptosis (20). C27 does not affect telomerase activity. The unclearly illustrated mechanisms include the induction of telomere dysfunction (1...

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Human telomerase reverse transcriptase regulates MMP expression independently of telomerase activity via NF‐κB‐dependent transcription

Cited by 117 publications

References 37 publications

TERT biology and function in cancer: beyond immortalisation

TERT biology and function in cancer: beyond immortalisation

Noncanonical Functions of Telomerase: Implications in Telomerase-Targeted Cancer Therapies

Antitumor effect of COOH-terminal polypeptide of human TERT is associated with the declined expression of hTERT and NF-κBï¿½p65 in HeLaï¿½cells

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