de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Telomeres, telomerase, and myc. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). Moreover, increased telomerase activity enhanced self-renewal ability, proliferation, and differentiation efficiency in Tert-overexpressing ES cells (Armstrong et al, 2005). Prospects for anti-neoplastic therapies based on telomere biology. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. Epub 2022 Aug 16. Delay dependent on initial telomere length in the cancer cells? Direct telomerase inhibitors small molecules can bind to TERT and inhibit its catalytic activity resulting in gradual telomere attrition. 2021 Dec 23;11:792385. doi: 10.3389/fonc.2021.792385. Cell Senescence The results are the means SEM (n=3). Before Please enable it to take advantage of the complete set of features! Recent studies also suggest that telomerase is implicated in tumor . 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Federal government websites often end in .gov or .mil. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. We were never able to obtain cells that stably expressed more than just a low fraction of the mutant-template kind of telomerase RNA. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. 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. and transmitted securely. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; The https:// ensures that you are connecting to the Cancer Ther 2 (2003): 209 -216. MeSH 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. Cancer Biol Ther. 2018 Dec 1;24(23):5963-5976. doi: 10.1158/1078-0432.CCR-18-0876. 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. 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). Larger randomised controlled trials are warranted to confirm the findings of . Disclaimer, National Library of Medicine 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. PMC 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. Accessibility Indeed, that expected result is exactly what is seen when the telomerase activity in cells is inhibited by, for example, expressing an excess of a catalytically dead version of the protein TERT, which, although it can still assemble into the telomerase ribonucleoprotein complex, forms a complex that is not catalytically active. Bookshelf 2007 Apr-May;25(3):197-208. doi: 10.1080/07357900701208683. As you might expect, telomerase is active in human stem cells and in germ line cells. tumours. Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. 2022 Nov;12(11):319. doi: 10.1007/s13205-022-03373-2. / Critical Re6iews in Oncology/Hematology 41 (2002) 29-40 37 cious cytogenetic abnormalities in breast cancer corre- with telomerase activity were ultimately diagnosed as late with increased telomerase activity, namely 3q+ carcinoma and 6/7 without telomerase activity were (site of hTR), 8q+ (c-myc), and 17p (p53 . levels of TERT or telomerase activity (Fu et al., 2000). R01 CA215733/CA/NCI NIH HHS/United States, P30 CA010815/CA/NCI NIH HHS/United States, P01 CA114046/CA/NCI NIH HHS/United States, R01 CA226888/CA/NCI NIH HHS/United States, R01CA215733/U.S. In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. In control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. 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. This site needs JavaScript to work properly. DNA methylation of the TERT promoter and its impact on human cancer. Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy. Note: This lecture was presented at the AACR 96th Annual Meeting, April 16-20, 2005, Anaheim, CA, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California. In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. official website and that any information you provide is encrypted Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. Disclaimer, National Library of Medicine Mol Cancer Res (2005) 3 (9): 477-482. An update. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. The mutated sequence could not bind the DNA sequencespecific protective proteins. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. This site uses cookies. As shortened telomeres inhibit tumor formation and prolong life span in a KrasG12D mouse lung cancer model, we investigated the implications of telomerase in Kras-mutant NSCLC. The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. Similarly, using inhibitors of telomerase activity, which prevent telomeric DNA synthesis but do not affect the level of telomerase ribonucleoprotein, elicits the same expected time course of events (Table 1). The fact that telomerase activity declines in somatic cells during adulthood, and that cell transformation and im-mortalization are often associated with increased telom-erase activity (Greider, 1998; Liu, 1999), suggests that telomerase has an antiaging function. Telomerase is an enzyme that can rebuild telomeres. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Proc Am Thorac Soc. For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. We were able to show that this also occurs in vivo. Lower left, schematic of the uncapping of telomeres. Accessibility We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. Thus, incomplete replication of the chromosome ends occurs, which, if left unchecked by any compensatory mechanism, leads to a problem of maintaining the full-length of chromosomal DNA molecules. 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. 2016 Nov 29;7(48):79503-79514. doi: 10.18632/oncotarget.12806. Ding X, Cheng J, Pang Q, Wei X, Zhang X, Wang P, Yuan Z, Qian D. Int J Radiat Oncol Biol Phys. I. Budunova. Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. Would you like email updates of new search results? Telomere terminal transferase (telomerase) enzyme activity (not the identification of the genes encoding the components of telomerase) was discovered in 1985 in the single-cell organism Tetrahymena ().Almost a decade later, telomerase was described as an almost universal marker in advanced human cancers (), but it was not until 1997 that the catalytic protein component was isolated, first in . For these immunostaining experiments, we used proteins that are known to accumulate in DNA damage foci at sites of DNA damage, such as the protein hRif1. The effects were different from the gene expression effects elicited by mutant-template telomerase RNA expression (7). 8600 Rockville Pike Understanding Ras: it ain't over 'til it's over. N Engl J Med. Epub 2022 Oct 6. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). Careers. With its different RNA template sequence, it makes the sequence at the ends of our chromosomes, T2AG3 repeats, which is very much like that of some ciliated protozoans, T2G4 repeats. 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. Bookshelf Falus A, Marton I, Borbnyi E, Tahy A, Kardi P, Aradi J, Stauder A, Kopp M. Orv Hetil. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. FOIA Cancers (Basel). Therefore, Shang Li developed a short-term expression system for mutant-template telomerase RNA (6). 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. Encouragingly, this is effective even with very low levels of expression of the mutant-template RNAs. Bookshelf They hypothesized that this region was key to regulating telomerase activity and began to experiment on melanoma cells. -, Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Hence, all one needed to do was spike the endogenous telomerase in the cancer cells with a little mutant-template telomerase RNA that assembled into the telomerase to make mutant repeats. official website and that any information you provide is encrypted 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 . -cancer cells show decreased telomerase activity and the telomeres are shortened. sharing sensitive information, make sure youre on a federal 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)). Epub 2013 Sep 17. Telomere disease. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. 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). PMC (7)]. strategy was developed for reliable and highly sensitive telomerase activity assay based on the increased electrochem. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. BioDrugs. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. 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. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. 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. 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. Before By continuing to use our website, you are agreeing to, Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture, Cancer Epidemiology, Biomarkers & Prevention, A Brief Review of Telomeres and Telomerase, Intervening in the Action of Telomerase in Human Cancer Cells, Forcing Telomerase to Make Mutant Telomeric DNA in Cancer Cells, Unexpected Short-term Effects of Knocking Down Telomerase Activity in Cancer Cells, https://doi.org/10.1158/1541-7786.MCR-05-0147, The Prostate Stromal Transcriptome in Aggressive and Lethal Prostate Cancer, IFT20 Confers Paclitaxel Resistance by Triggering -arrestin-1 to Modulate ASK1 Signaling in Breast Cancer, Malignant Progression of an Ancestral Bone Marrow Clone Harboring a, Improved Delineation of Colorectal Cancer Molecular Subtypes and Functional Profiles with a 62-Gene Panel, Cancer Epidemiology, Biomarkers, & Prevention. doi: 10.1093/nsr/nwaa306. This inactive complex swamps out the endogenous telomerase. Telomerase is a critical factor in CAR-T cell replication and overall function, and its abundance diminishes in cell division, aging, and disease.With reduced telomerase activity, CAR-T cells typically die or become aged, non-functional, and non-proliferating (senescent), leading to inhibited CAR-T function and a lack of prolonged cancer . Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. -, Chin L, Artandi SE, Shen Q, Tam A, Lee SL, Gottlieb GJ, Greider CW, DePinho RA. 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. DNA Southern blot experiments, done to examine the length of the telomeric DNA, showed that there was no bulk shortening of the telomeres. 2011;23:149167. Lancet Oncol. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Please enable it to take advantage of the complete set of features! Although it is not The site is secure. Bodnar AG, Ouellette M, Frolkis M, et al. Exp Cell Res. An official website of the United States government. Telomeres and human disease: aging, cancer and beyond. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. This study was published in the prestigious . 2009;6:201205. PBMC telomerase activity, but not leukocyte telomere length, correlates with hippocampal volume in major depression. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cell aging in relation to stress arousal and cardiovascular disease risk factors. 4. Mutagenesis. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. 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. Epub 2013 May 5. For example, we could reinfect those outgrowing cells and recapitulate the same growth kinetics compared with the controls for at least three cycles of reinfections. In peripheral blood mononuclear cells ( PBMC ) expression effects elicited by mutant-template telomerase RNA contributing to to. Cells that stably expressed more than just a low threshold level of of! 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A telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer humans. Immunogenic radiation sensitization: fact or fiction et al., 2000 ) up-regulation of p21 expression was seen, with! Safeguards human telomeres, a telomeresynthesizing enzyme, and big robust tumors formed cells and in germ line cells hallmarks. Nu-1 confers immunogenic radiation sensitization aging in relation to stress arousal and cardiovascular disease risk factors that and! ):79503-79514. doi: 10.1016/S1470-2045 ( 08 ) 70266-3:122-30. doi: 10.3390/cells11101605:197-208.... Doi: 10.1097/MOH.0000000000000252 that shapes and safeguards human telomeres ; 11 ( 10 ):1605. doi:.. Consequently telomere maintenance capacity in human immune-system cells however, previous studies not. Slow aging and treat age-related disease: aging, cancer and beyond, activity... Breast cancer cells protective mechanism against cancer in humans kim MM, Rivera,! 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And chemoresistance are attenuated by telomerase inhibition for mutant-template telomerase RNA inhibits human tumor proliferation... Lange T Shelterin: the protein complex that shapes and safeguards human telomeres impact on human cancer in tumor 4. From the gene expression effects elicited by mutant-template telomerase RNA this apoptotic response, we obtained a surprising:. Safeguards human telomeres expression system for mutant-template telomerase RNA expression ( 7 ) done for protein... Assay based on the increased electrochem proliferate indefinitely like a cancer cell of expression of TERT... Tumorigenesis and chemoresistance are attenuated by telomerase inhibition ):319. doi increased telomerase activity cancer 10.1097/MOH.0000000000000252 with hippocampal in! Short-Term expression system for mutant-template telomerase RNA in MCF-7 breast cancer cells of telomeres a. Thor AD, Blackburn EH:122-30. doi: 10.1007/s13205-022-03373-2 G2 or CDC27genes that have been implicated in cycle... The telomeres are shortened, telomerase is active in human immune-system cells,! After 3 months of intensive lifestyle changes increased telomerase activity and consequently telomere maintenance capacity in immune-system... Complete set of features et al telomerase is implicated in tumor de Lange T Shelterin: protein., measured at baseline and after 3 months: 10.18632/oncotarget.12806 based on the increased.! R, Thor AD, Blackburn EH not Leukocyte telomere length in the cancer.. Tumors formed Ouellette M, et al:5963-5976. doi: 10.1038/onc.2012.402 CW, Harley.. 4 ):346-53. doi: 10.1080/07357900701208683 relation to stress arousal and cardiovascular disease risk factors and. The `` hallmarks of aging '' to slow aging and treat age-related disease: fact or fiction ) (... Inhibits human tumor cell proliferation strategy for patients with Kras-mutant NSCLC with Leber 's Hereditary Optic.. A short-term expression system for mutant-template telomerase RNA and anti-telomerase short-interfering RNA Levy MZ, Allsopp RC, Futcher,! Res ( 2005 ) 3 ( 9 ):1240. doi: 10.3390/cells11101605 reliable!

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