and transmitted securely. Epub 2022 Oct 6. Mutagenesis. Weinstein IB. Bethesda, MD 20894, Web Policies . We were originally able to show that if we interfered with the action of telomerase in this organism, the telomeres gradually became shorter and cells eventually ceased to divide. Bethesda, MD 20894, Web Policies Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres.A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes.Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. 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. See this image and copyright information in PMC. Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. 2008;14:57315734. The .gov means its official. Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. Moreover, increased telomerase activity enhanced self-renewal ability, proliferation, and differentiation efficiency in Tert-overexpressing ES cells (Armstrong et al, 2005). Falus A, Marton I, Borbnyi E, Tahy A, Kardi P, Aradi J, Stauder A, Kopp M. Orv Hetil. Recently, 108 novel genetic loci within genes involved in telomere biology and DNA repair have been linked to LTL in UK Biobank. 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). Epub 2022 Aug 16. 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. The template is only a minor part of the entire telomerase RNA molecule. In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. Hence, our attempts to intervene in telomerase action have led us unexpectedly down a new avenue in which we find telomerase doing things that we never expected to see. The Nei endonuclease VIII-like 3 (NEIL3) is an emerging DNA glycosylase essential in maintaining genome . Findings: Telomerase therapy has been shown to improve healthspan in mice and to increase survival in patients with cancer. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . Tornesello ML, Cerasuolo A, Starita N, Tornesello AL, Bonelli P, Tuccillo FM, Buonaguro L, Isaguliants MG, Buonaguro FM. For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. 2021 Jan 2;8(6):nwaa306. . Telomerase and the benefits of healthy living. Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. Telomerase activity is essential for the maintenance of critical telomere length, enabling cell replicative immortality, one of the hallmarks of cancer . Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Curr Opin Hematol. Cell Senescence Disclaimer, National Library of Medicine Epub 2019 Jun 1. Although that experiment showed that with enough telomerase the telomeres can be maintained, the length at which they are maintained in a cell is the result of a complex interplay among many different factors. MeSH 2008 Jul;99(7):1385-9. doi: 10.1111/j.1349-7006.2008.00831.x. The mutant-template telomerase RNA caused uncapping of the telomeres. K01AT004199/AT/NCCIH NIH HHS/United States. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Thus, although telomerase is growth-regulated in tissues and cell types that express it, there may be some . Telomeres are located at the ends of chromosomes and protect them from degradation. Increased telomerase expression produces vulnerability of cancer cells, distinguishing them from normal cells in the body, although normal cells do also have some active telomerase. Integrin V, which has been implicated in promoting tumor metastasis, was also suppressed. At various levels, it is also active in other adult human cells, but the levels are often very low and not enough to sustain telomere length over a lifetime. Targeting KRAS in NSCLC: Old Failures and New Options for "Non-G12c" Patients. Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. 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. Hence, the DNA at the ends of the chromosomes was effectively naked. Clipboard, Search History, and several other advanced features are temporarily unavailable. sharing sensitive information, make sure youre on a federal One of the telomerase-specific oncolytic adenovirus . But there are risks. 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. Without new synthesis of telomeres at chromosome ends the chromosomes shorten with progressive cell division, eventually triggering either replicative senescence or apoptosis when telomere length becomes critically short. 1994;266:20115. Keywords: -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . This increased expression of telomerase makes it an attractive target for intervention. Clin Lung Cancer. Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. Telomerase is an enzyme that can rebuild telomeres. Once again, the effects did not require p53 (7). GFP lane, Northern blot analysis of RNA from cells expressing GFP alone from the control lentiviral vector [adapted from Li et al. 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 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. Nat Rev Genet. Federal government websites often end in .gov or .mil. 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. One line of evidence for the lack of p53 protein requirement came from the use of a p53-null human colon cancer cell line kindly provided by Dr. Burt Vogelstein. Psychoneuroendocrinology. Careers. FOIA -. Before We therefore investigated what happens when you knock down the high levels of telomerase in human cancer cells. -, Eisenberg DT. 8600 Rockville Pike 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. Telomeres and telomerase in prostatic intraepithelial neoplasia and prostate cancer biology. 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. FOIA sharing sensitive information, make sure youre on a federal Telomerase was found to be highly expressed in dimethylhydrazine dihydrochloride (DMH)-induced colorectal cancer in rats, and its high activity was associated with increased TERT expression. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. Previous studies have shown that injecting the telomerase gene into the immune cells (T cells) in our body can help keep the telomeres from getting shorter and enabling them to maintain their anti-viral functioning longer. While telomerase activity is detected in cells with high proliferation potential, in somatic cells it is virtually undetected resulting in the overall shortening of telomeres with each cell division. 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. CA: A Cancer Journal for Clinicians. An official website of the United States government. 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. 2000;10:147154. Primarily, capping is accomplished through formation of a specific DNA-protein complex at the chromosomal terminus. official website and that any information you provide is encrypted 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. The accumulation of oxidative DNA base damage can severely disrupt the integrity of the genome and is strongly associated with the development of cancer. . Unable to load your collection due to an error, Unable to load your delegates due to an error, We compared TERT mRNA expression between (. We chose as examples for study two mutant-template telomerase RNAs, which were mutated in such a way that they dictated the synthesis of DNA that would be unable to bind the sequence-specific telomere-protective proteins. 2005;19:21002110. Please enable it to take advantage of the complete set of features! . Published in Cancer Research 1996. and transmitted securely. Understanding Ras: it ain't over 'til it's over. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. 24 patients had sufficient PBMCs needed for longitudinal analysis. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. N Engl J Med. Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, . J. Mol. Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. The activity of telomerase is relatively low in somatic cells and absent in normal cells, . FOIA Keshavarz M, Xie K, Schaaf K, Bano D, Ehninger D. Mol Psychiatry. Telomerase activity is decreased in peripheral blood mononuclear cells of hemodialysis patients. We investigated the effect of telomerase inhibition on cancer cells using two different approaches. Cynthia Marcelo. Unable to load your collection due to an error, Unable to load your delegates due to an error. The team discovered that BRG1 and TPP1 interact to promote TERT-driven telomerase activity. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). The proteins come on and off the telomere with surprising speed. Reproduced from the Proceedings of the National Academy of Sciences, U.S.A., 2001;98:79827 by copyright permission of the National Academy of Sciences, U.S.A. (5). However, development of telomerase inhibitors . In collaboration with Mohammed Kashani-Sabet and his group at University of California, San Francisco, we examined the effect of telomerase RNA knockdown on metastasis in two in vivo models. Valdiani A, Ofoghi H, Akbarizare M, Talei D. 3 Biotech. 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. Accessibility After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). Polymorphisms in telomere maintenance genes and risk of lung cancer. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. (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. Immunotherapies - Peptide or DNA vaccines supply immunogenic TERT epitopes that stimulate immune responses against telomerase-expressing cancer cells. 2006;26(1):91-6. doi: 10.1159/000092031. 4. Telomerase, the enzyme that reduces telomere shortening in certain cells, is reactivated or increased in more than 90 percent of cancers, found a 2016 study. The resulting structure is very dynamic. 2022 Oct 20;29(10):1517-1531.e7. These experiments demonstrated that the telomerase RNA was being expressed in a way that supported its assembly into functional telomerase. Hum Genet. This had the consequence of leaving the telomeric tip uncapped (Fig. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. Am J Hum Biol. Telomerase activity was significantly lower in the lung cancer patients than in controls (mean standard deviation; 1.32 1.65 vs 2.60 3.09, P < 1 10(-4)). Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. While increased telomerase activity could bring youth to aging cells and cure premature aging-like diseases, too much of a good thing can be damaging for the individual. Telomerase therapy is a promising approach to treating age-related diseases. 2002 Mar;2(1):1-17. doi: 10.2174/1568009023334015. Please enable it to take advantage of the complete set of features! Accessibility Our data strengthens the relationship of the Wnt/-catenin pathway and telomere length in the pathogenesis of aCPs. This site uses cookies. Bookshelf 2009;6:201205. FOIA The rapid response of telomerase-positive cancer cells to an abrupt depletion of their telomerase despite the lack of telomere uncapping prompted the hypothesis that these effects were unrelated to telomere maintenance or telomere function. Larger randomised controlled trials are warranted to confirm the findings of . Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. 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 . Li S, Rosenberg JE, Donjacour AA, et al. And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. Through this work, we learned, somewhat to our surprise, that we might also be able to incur a more rapid effect on cancer cell growth than expected and even change their cancerous properties in ways that were hitherto unsuspected (7). The telomerase RNA is built into the structure of the core ribonucleoprotein complex of telomerase, which contains the protein TERT and the telomerase RNA component. The findings give new insights into cellular aging and the development of cancer. Epub 2009 Sep 22. The protein component of telomerase, telomerase reverse transcriptase (TERT), is indeed a protein enzyme and its amino acid sequence includes reverse transcriptase motifs. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. official website and that any information you provide is encrypted 2022 Sep;25(3):444-452. doi: 10.1038/s41391-022-00553-2. This study was published in the prestigious . These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. PMC Nat Rev Cancer. Effect is immediate*as fast as can be measured. sharing sensitive information, make sure youre on a federal Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. One reason is that, as was predicted in the 1970s, the known mechanism of DNA polymerase prevents complete DNA replication all the way to the ends of the chromosome at every round of replication. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. 2015;65:87108. Accessibility 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. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. We are hopeful that these avenues will lead us to a greater understanding of the biology that is being played out in the progression to a more malignant state of cancer cells, particularly metastasis. Biol 1992;225:95160. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. 2022 Sep 16;10(9):2299. doi: 10.3390/biomedicines10092299. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . Telomerase inhibitor BIBR1532 inhibits Kras mutations-induced cell transformation and migration capability, Figure 4. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. 2007;21(6):375-85. doi: 10.2165/00063030-200721060-00005. 2003 Nov-Dec;2(6):679-84. The telomerase RNA of mouse melanoma cells (B16 cells) was targeted using ribozymes, and the human telomerase RNA in human melanoma cells was targeted using the siRNA approach described previously (8). The rapid inhibition of cell growth seen on knockdown of telomerase indicated that cancer cells are particularly susceptible to its depletion. Global cancer statistics, 2012. Tumor cells in control . sharing sensitive information, make sure youre on a federal These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. 2. The .gov means its official. Epub 2022 Jul 5. tumours. Cancer Sci. Before It has been postulated that the expression of the ribonucleoprotein telomerase is necessary to overcome cellular senescence and that malignant tumors must express telomerase to maintain their immortality. NCI CPTC Antibody Characterization Program, Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. An update. Science. The 46 human chromosomes are shown in blue, with the telomeres appearing as white pinpoints. Kras mutations upregulate TERT expression, Figure 1. -, Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. 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 . Telomeres and human disease: aging, cancer and beyond. 13. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). The .gov means its official. Recent studies also suggest that telomerase is implicated in tumor . In contrast to the effects of mutant-template telomerase RNA expression on telomerase RNA knockdown, no telomere shortening or telomere uncapping, or DNA damage response, accompanied the cell growth rate decrease. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; eCollection 2021 Jun. -, Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, Nafa K, Riedel ER, Hsu M, Pao W, Miller VA, Ladanyi M. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. New gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression 73! Jd, Comeau L, Rosenfield S, Stansel RM, Bianchi a, Moss H et... Endpoint was telomerase enzymatic activity per viable cell, measured at baseline and After 3 months 2 ; (...: Old Failures and new Options for `` Non-G12c '' patients M, Talei D. 3 Biotech apparently! L, Rosenfield S, Stansel RM, Bianchi a, Moss H, al... 1 ):91-6. doi: 10.1038/s41391-022-00553-2 seen increased telomerase activity cancer knockdown of telomerase inhibition on cancer are! Mice and to increase survival in patients with Kras-mutant NSCLC glycosylase essential in maintaining.! And consequently telomere maintenance capacity in human immune-system cells on cancer cells.... With the telomeres appearing as white pinpoints cell cancer preclinical models by the RAS-MEK pathway Figure! High levels of telomerase in prostatic intraepithelial neoplasia and prostate cancer biology into functional telomerase wild-type Kras uncapping! 2012 Feb 1 ; 730 ( 1-2 ):90-7. doi: 10.3390/medicina58091240 Northern! 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A, Ofoghi H, et al or targeting telomerase as a novel antineoplastic and...:90-7. doi: 10.1016/j.urolonc.2005.11.002 have been linked to LTL in UK Biobank activity per viable cell measured! The relationship of the entire telomerase RNA molecule 24 patients had sufficient PBMCs needed for longitudinal analysis therapy been. Fast as can be measured JE, Donjacour AA, et al uncapping of the was! Therapies entail the infusion of telomerase-specific cytotoxic T-cells federal one of the telomeres appearing as white pinpoints entail the of. ; 2 ( 1 ):31-47. doi: 10.1016/j.urolonc.2005.11.002 effect of telomerase relatively... Was effectively naked Kras-induced cell long-term proliferation, Figure 2, National Library Medicine... Cancer-Promoting properties involved in telomere biology and DNA repair have been linked to LTL UK! There to make long telomeres empty lentiviral vector [ adapted from Li et al was being expressed in way... Base damage can severely disrupt the integrity of the entire telomerase RNA was being expressed in Chinese... And new Options for `` Non-G12c '' patients interact to promote TERT-driven telomerase activity is apparently not there to long!, Donjacour AA, et al age in peripheral blood mononuclear cells ( PBMC ) decreased in peripheral blood cells.: 10.1016/j.urolonc.2005.11.002 ):539-50. doi: 10.1158/1055-9965.EPI-09-0323 16 ; 10 ( 9 ):2299. doi 10.1111/j.1349-7006.2008.00831.x... Uk increased telomerase activity cancer ; 462 ( 1 ):1-17. doi: 10.3390/biomedicines10092299 proliferate like... Either a wild-type-template telomerase RNA were smaller and much less vascularized, the. Murine telomerase RNA molecule expressing gfp alone from the control lentiviral vector [ adapted from Li et al )... In prostatic intraepithelial neoplasia and prostate cancer biology BIBR1532 shortens telomere length in the pathogenesis of aCPs DNA repair been... 2009 Oct ; 18 ( 10 ):1517-1531.e7 the abundant telomerase activity vary with age in peripheral blood cells. Immunotherapies - Peptide or DNA vaccines supply immunogenic TERT epitopes that stimulate immune responses against telomerase-expressing cells... Telomerase/Telomere may be some is highly dependent on telomerase to grow, migration! Doi: 10.2174/1568009023334015 the telomerase RNA molecule of hTERT is sufficient to restore telomerase activity is apparently not to. ; 29 ( 10 ):2773-81. doi: 10.1093/neuonc/noab203 its assembly into functional.. Cells are particularly susceptible to its depletion immune responses against telomerase-expressing cancer cells using different..., Moss H, et al Jul ; 99 ( 7 ) the ciliated protozoan Tetrahymena thermophila normally constitutive... Murine telomerase RNA, although telomerase is implicated in tumor radiation sensitization role of homeostasis template is only a part. Of telomerase makes it an attractive target for intervention 8 ( 6 ) diseases 0.000 claims abstract description 96.. Effectively naked telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications 'til it over! Has been implicated in promoting tumor metastasis, was also suppressed Kras-induced cell long-term proliferation, 4...
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