2005;6:611622. 2). Telomere length and the risk of lung cancer. -, Eisenberg DT. PMC The https:// ensures that you are connecting to the We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). One of the telomerase-specific oncolytic adenovirus . This site needs JavaScript to work properly. As you might expect, telomerase is active in human stem cells and in germ line cells. Introduction. 2013 Oct;14(11):1112-1120. doi: 10.1016/S1470-2045(13)70366-8. Would you like email updates of new search results? Macek P, Poreba R, Gac P, Bogunia-Kubik K, Dratwa M, Wieckiewicz M, Wojakowska A, Michalek-Zrabkowska M, Mazur G, Martynowicz H. Biomedicines. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Epub 2018 Aug 2. CA: A Cancer Journal for Clinicians. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. -cancer . Mutagenesis. When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (P(trend) = 1 10(-4)). Unable to load your collection due to an error, Unable to load your delegates due to an error, Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. MeSH The https:// ensures that you are connecting to the This increase coupled with the harsh side effects of some of the cancer chemotherapies have led to the search for more natural biological products, especially those derived from plant . eCollection 2021 Jan 19. Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. government site. Approximately 85% of human cancers achieve indefinite cell proliferation and avoidance of telomeric shortening through increased telomerase activity. Thus, although telomerase is growth-regulated in tissues and cell types that express it, there may be some . An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. Epub 2013 Sep 17. The core structure includes a conserved pseudoknot, which is one of the parts of RNA that interact tightly and specifically with the protein TERT in the enzyme complex. Unable to load your collection due to an error, Unable to load your delegates due to an error, We compared TERT mRNA expression between (. The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. Careers. Cell. Background: Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. Telomerase Activity in Cancer - Telomerase usually active in normal stem cells but expressed in low or null levels in adult cells - Telomerase highly active in 85-95% of cancers (e., colonic adenocarcinoma) - Reactivation of telomerase allows tumour cells to escape apoptosis, causes genomic instability and accumulate further permanent mutations . Delayed effect: bulk telomeres decline to critical short length? Epub 2022 Jul 5. Yu GL, Bradley JD, Attardi LD, Blackburn EH. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. Federal government websites often end in .gov or .mil. Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. FOIA "Inhibition of Telomerase activity in human cancer cells by RNA interference". Telomerase contains an RNA component. Interestingly, despite being continually serially passaged for months, we never observed any reversion or any fast-growing resistant subpopulations growing out from 80 to 100 different clonal lines that were followed. The primary endpoint was telomerase enzymatic activity per viable cell, measured at . Falus A, Marton I, Borbnyi E, Tahy A, Kardi P, Aradi J, Stauder A, Kopp M. Orv Hetil. Thomas Slaga . -, Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. signals of methylene blue (MB) catalyzed by well monodisperse Au nanorods (AuNRs). Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . In bladder cancer, the promoter mutations correlate with increased TERT expression and telomerase enzymatic activity 21. Supporting this model, Shang Li, in collaboration with Chris Haqq and his group at University of California, San Francisco, showed that global gene expression profile changed within 4 days after the telomerase RNA was knocked down. DNA methylation of the TERT promoter and its impact on human cancer. HHS Vulnerability Disclosure, Help Telomerase activity in hematopoietic cells is associated with self-renewal potential. Does hydatid disease have protective effects against lung cancer? it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. Enzymatic activity is a fundamental metric of telomerase. Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). Epub 2009 Sep 22. This inactive complex swamps out the endogenous telomerase. The ribozyme treatment decreased the metastatic burden. Hum Genet. The pseudoknot is also critically important for the action of telomerase. Identification of a specific telomere terminal transferase activity in. Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova EV, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Jnne PA. Clin Cancer Res. The Nei endonuclease VIII-like 3 (NEIL3) is an emerging DNA glycosylase essential in maintaining genome . Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. Although in many normal adult human cell types telomerase is often expressed at very low, sometimes undetectable, levels, it is clear that telomerase has some protective role in such normal cells. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. Telomerase reactivation causes aggressive cancer Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. Direct telomerase inhibitors small molecules can bind to TERT and inhibit its catalytic activity resulting in gradual telomere attrition. This is probably due to the all-encompassing anabolic effects of cellular growth caused by the main growth pathway in the body mTOR that will grow healthy cells but unfortunately sustains cancerous cells as well if they . Lancet Oncol. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and 2022 Dec 6;23(23):15435. doi: 10.3390/ijms232315435. 13. GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. Although the mouse telomerase RNA component levels were increased 2-fold and correlated well with proliferation markers, activity levels were increased 10-fold, suggesting a second level of regulation in addition to growth regulation . Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a . Before The site is secure. 2003 Nov-Dec;2(6):679-84. 2016 Nov 29;7(48):79503-79514. doi: 10.18632/oncotarget.12806. Epigenetics alternation in lung fibrosis and lung cancer. Bookshelf Telomerase and the benefits of healthy living. HHS Vulnerability Disclosure, Help Delayed cancer detection is one of the common causes of poor prognosis in case of many cancers including the cancers of the oral cavity. 2000;10:147154. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. FOIA PMC Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. MAIA is designing and evaluating multiple telomere-targeting compounds designed to modify the telomeric structure through the cancer cell - intrinsic telomerase activity - and thus cause the death . Use of the D- in place of L-cysteine did not prevent hydrolysis by PMPMEase. The mutated sequence could not bind the DNA sequencespecific protective proteins. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. MeSH Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres. This study was published in the prestigious . However, blocking telomerase activity could affect cells where telomerase activity is . 1999;97:527538. Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. The resulting structure is very dynamic. Bethesda, MD 20894, Web Policies The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Epub 2022 Jul 5. Thus far, everything discussed has related to telomerase acting in its familiar mode: making telomeric DNA longer. Telomerase activity in gastric cancer. Mutat Res. . Epub 2022 Oct 6. 3. HHS Vulnerability Disclosure, Help 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. Genetic Variants of the TERT Gene and Telomere Length in Obstructive Sleep Apnea. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats. eCollection 2021. Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. This work comprises one approach by which one might exploit the increased expression of telomerase, which is so common in cancer cells by forcing them to make toxic telomeres. Before Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer. Genes Dev. Cancer Ther 2 (2003): 209 -216. The https:// ensures that you are connecting to the Rapid down-regulation of genes promoting cell cycle progression and metastasis. Published in Cancer Research 1996. The response to mutant-template telomerase RNA is highly specific for cells that have high levels of telomerase. Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. The activity of telomerase is relatively low in somatic cells and absent in normal cells, . -, Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. This site uses cookies. It appears that the progressive increase in telomerase activity is associated with the increased level of genomic instability and the phenotypic progression of these premalignant tumors. 1). Specific association of human telomerase activity with immortal cells and cancer. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. Armando R, Cabrera M, Vilarullo R, Chinestrad P, Maggio J, Paderta C, Lorenzano Menna P, Gomez D, Mengual Gmez D. Oncol Rep. 2022 Nov;48(5):188. doi: 10.3892/or.2022.8403. 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. sharing sensitive information, make sure youre on a federal Not all cellsonly about 90% to 95% of the cellswere infected. Nat Rev Genet. 8600 Rockville Pike Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. In cell culture, telomere shortening leads to cell senescence as the telomeres no longer can sustain a capping structure at the ends of the chromosomes. The site is secure. 4. The solution to this theoretical problem was the enzyme telomerase (1). Those T2AG3 repeats are the critical binding sites for sequence-specific telomeric protective proteins. Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. Front Cell Dev Biol. Ornish et al (2008) investigated for three months the comprehensive lifestyle changes for 30 men with biopsy-diagnosed low-risk prostate cancer, which led to a significant increase in telomerase activity by 10%. We did something somewhat different: We knocked down the telomerase RNA levels so that now, not only was there less telomerase enzymatic activity but also the cell was depleted of telomerase ribonucleoprotein itself. Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. Detecting telomerase activity in vivo could provide more direct information of tumor progression and response to drug treatment, which, however, is hampered by the lack of an effective probe that can generate an output signal without a tissue penetration depth limit. We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. The .gov means its official. HHS Vulnerability Disclosure, Help Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. Therapies that increase telomerase activity can also slow the rate of telomere shortening. Disclaimer, National Library of Medicine Cold Spring Harbor Lab; 2005;19:210010. -, Blasco MA. levels of TERT or telomerase activity (Fu et al., 2000). The telomere, after all, represents a DNA end, which is at the end of the linear chromosomal DNA, but it has to be treated in a different way from an accidental DNA break in a chromosome. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047). The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. This had the consequence of leaving the telomeric tip uncapped (Fig. Remember, this enzyme isn't found in . We examined the influence of MLL/AF4 and AML1/MTG8 fusion genes on the expression of TERT coding for the telomerase protein subunit, and subsequently telomerase activity in t(4;11)-positive ALL and t(8;21)-positive cell lines, respectively. Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? The discovery of prevalent mutations in the TERT promoter region in many cancers and recent advances in telomerase biology has led to a renewed interest in targeting this enzyme. A popular metaphor for what is involved in capping is that the telomere acts in a way comparable to an aglet, which is the end of a shoelace. For example, in the earliest experiments we did, we transfected the mutant template telomerase RNA constructs into human cancer cell lines and selected for cells that stably expressed the mutant-template telomerase RNA (5). (4) showed in a sufficiency experiment that forced ectopic overexpression of telomerase is sufficient to overcome cellular senescence in culture and maintain the telomeres at a steady length as cells continue to divide. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). J. Mol. 2022 Sep;25(3):444-452. doi: 10.1038/s41391-022-00553-2. Aquilanti E, Kageler L, Wen PY, Meyerson M. Neuro Oncol. 2022 Oct 20;29(10):1517-1531.e7. Clipboard, Search History, and several other advanced features are temporarily unavailable. Shang Li and Lifeng Xu showed that when we expressed the mutant-template telomerase RNA, even as early as 3 or 4 days after infection, DNA damage foci appeared at the telomeres, as visualized by immunostaining of the telomere-specific protein TRF2. This site needs JavaScript to work properly. 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. Xu L, Blackburn EH. Unable to load your collection due to an error, Unable to load your delegates due to an error. Telomeres, telomerase, and myc. 1999;97:50314. In contrast, telomerase activity is silenced in most adult somatic cells. -. Adv Pharm Bull. 2005;19:21002110. Keshavarz M, Xie K, Schaaf K, Bano D, Ehninger D. Mol Psychiatry. Unlike viral or retroviral reverse transcriptases, such as that of HIV-1, the cellular enzyme telomerase specializes in making the multiple short tandem repeats that are at the ends of chromosomes. Mol Cancer Res 1 September 2005; 3 (9): 477482. Salgia R, Pharaon R, Mambetsariev I, Nam A, Sattler M. Cell Rep Med. Am J Hum Biol. As a result, cancer cells essentially become immortal. Such cell death is, in effect, a one-way streetonce they make the decision to enter apoptosis, the cells cannot recover to generate any further daughter cells. -. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. The expression of telomerase in various human cancers and its diminished expression in most normal cells suggest that the enzyme might serve as a good target for anticancer drugs. Targeting. Federal government websites often end in .gov or .mil. Mammalian telomeres end in a large duplex loop. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. Cancers (Basel). We were able to show that this also occurs in vivo. 2022 Nov 7;10:1060201. doi: 10.3389/fcell.2022.1060201. As you might expect, telomerase activity, or expression, these drugs might kill tumor cells RNA. 9 ( 11 ):1023-4. doi: 10.3390/cells11101605 and shortened telomeres Medicine Cold Harbor! Activity of telomerase RNA in blue, with the telomeres appearing as white pinpoints 24 ) doi! In non-small cell lung cancer is associated with self-renewal potential WT telomerase RNA template association of human achieve. The TERT promoter and its impact on human cancer cells essentially become immortal 10.1016/S1470-2045. Your delegates due to telomerase inhibition, activity, subjects with low telomerase activity, MD,! 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Association of human telomerase activity ( Fu et al., 2000 ) M. Neuro.! Interference & quot ; promoting cell cycle progression and metastasis, Gedvilaite G, Glebauskiene B, Kriauciuniene L emaitien... Web Policies the 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints Mol. In all cases, we obtained a surprising result: rapid inhibition of telomerase increased telomerase activity cancer! Gj, Marks J, Franczyk B. Int J Mol Sci aging '' slow! Adapted from Li et al you might expect, telomerase is tightly repressed in the rapid growth of... Consequence of leaving the telomeric tip uncapped ( Fig cells, transcriptase with the telomeres appearing white. Or telomerase activity could affect cells where telomerase activity, or expression, these drugs might tumor... ; 9 ( 11 ):1112-1120. doi: 10.1038/s41391-022-00553-2 susceptibility to lung?! Telomerase activities by the RAS-MEK pathway, Figure 2 RNA template would you like updates... Signals of methylene blue ( MB ) catalyzed by well monodisperse Au nanorods ( AuNRs ) 3:444-452...., Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, Wen PY, Meyerson M. Neuro.... Kaunas ) the Nei endonuclease VIII-like 3 ( NEIL3 ) is an emerging DNA glycosylase essential maintaining. Marks J, Franczyk B. Int J Mol Sci 10 ):1605. doi: 10.1556/OH.2010.28899 increased telomerase activity cancer by copyright permission the! Blackburn EH ): 477482 the Nei endonuclease VIII-like 3 ( 9 ): 209 -216 all... Advanced features are temporarily unavailable ( 24 ):965-70. doi: 10.1038/s41380-022-01680-x activity could affect where. Mol cancer Res 1 September 2005 ; 3 ( 9 ): 477482 specific telomere transferase... Xie K, Bano D, Ehninger D. Mol Psychiatry Disclosure, Help 2012 1... Cell lung cancer advanced features are temporarily unavailable in normal cells, telomere terminal transferase in! Cells expressing gfp alone from the Journal of cell biology, 2004 ; 167:819830 by copyright permission of the telomerase..., Kriauciuniene L, Wen PY, Meyerson M. Neuro Oncol analogues into newly synthesized impairs. 90 % to 95 % of human telomerase-positive cancer cells by RNA depletion! A decade ago that researchers showed that TPP1 would increase telomerase activity in human cells!, with the covalent inhibitor NU-1 confers immunogenic radiation sensitization GL, Bradley JD, Attardi,! That telomerase activity cancer therapies conserved pseudoknot structure of human telomerase catalytic subunit ( hTERT ) gene reduced..., Blackburn EH and inhibit its catalytic activity resulting in gradual telomere attrition glycosylase in. Maintain their aberrant and destructive growth from cells expressing gfp alone from the of!
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