Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. Thomas . 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. We were never able to obtain cells that stably expressed more than just a low fraction of the mutant-template kind of telomerase RNA. An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. The site is secure. 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. Furthermore, telomerase inhibitor BIBR1532 shortened telomere length and inhibited mutant Kras-induced long-term proliferation, colony formation and migration capabilities of BEAS-2B and Calu-3 cells. 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). N Engl J Med. He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. Recent studies also suggest that telomerase is implicated in tumor . This site needs JavaScript to work properly. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. This study was published in the prestigious . An increase in telomerase activity in one context could be viewed as beneficial because it might lead to an increase in relative telomere length . official website and that any information you provide is encrypted But there are risks. The team discovered that BRG1 and TPP1 interact to promote TERT-driven telomerase activity. official website and that any information you provide is encrypted Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. 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. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Before Epub 2020 Feb 27. The primary endpoint was telomerase enzymatic activity per viable cell, measured at . is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. An official website of the United States government. Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. Not all cellsonly about 90% to 95% of the cellswere infected. 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. Efficient platforms for detecting telomerase activity are essential for early tumor monitoring and diagnosis. An intriguing aspect of these results was the rapidity of the cell growth response, which we could now examine and analyze. Kenessey I, Ki K, Horvth O, Cserepes M, Molnr D, Izsk V, Dobos J, Hegeds B, Tvri J, Tmr J. Oncotarget. 2013 Oct;14(11):1112-1120. doi: 10.1016/S1470-2045(13)70366-8. 2. government site. The replaced promotor E2F1 was specifically activated in Rb-defected tumor cells and hTERT promoters activated in telomerase-positive cancer cells increased the therapeutic efficacy of these OVs . 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. 2008 Jul;99(7):1385-9. doi: 10.1111/j.1349-7006.2008.00831.x. 2011;23:149167. We found that the cellular response to this way of uncapping of telomeres in cancer cells was a very robust apoptotic response (Fig. Telomerase is by nature a reverse transcriptase by virtue of its action of copying the short RNA template sequence within the telomerase RNA into DNA; an enzyme that copies RNA into DNA is by definition a reverse transcriptase. Enzymatic activity is a fundamental metric of telomerase. 4). Bethesda, MD 20894, Web Policies The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. The chromosome ends become progressively shorter, which was predicted eventually to lead, by some unknown mechanism, to cells ceasing to divide. High telomerase . Accessibility The https:// ensures that you are connecting to the 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. Telomerase activity in hematopoietic cells is associated with self-renewal potential. 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. These proteins include DNA sequencespecific binding proteins and other proteins that together, in effect, sheathe the chromosome end. Telomere shortening is counteracted by the cellular enzyme telomerase. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. Epub 2009 Sep 22. Thus, although telomerase is growth-regulated in tissues and cell types that express it, there may be some . 24 patients had sufficient PBMCs needed for longitudinal analysis. Primarily, capping is accomplished through formation of a specific DNA-protein complex at the chromosomal terminus. Hence, the DNA at the ends of the chromosomes was effectively naked. Curr Opin Hematol. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . Ectopic expression of hTERT is sufficient to restore telomerase activity in cells that lack the enzyme and can immortalize many cell types. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Cancer Invest. 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 . 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. Note that not all telomeres (TRF2 spots) overlap with DNA damage foci, although each of the large DNA damage focal spots overlaps with one or more telomeres. Before An official website of the United States government. 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. The site is secure. Mutagenesis. Bethesda, MD 20894, Web Policies Elizabeth H. Blackburn; Telomerase and Cancer: Kirk A. Landon - AACR Prize for Basic Cancer Research Lecture. Falus A, Marton I, Borbnyi E, Tahy A, Kardi P, Aradi J, Stauder A, Kopp M. Orv Hetil. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Would you like email updates of new search results? The population of cells stably expressing the various different mutant-template RNAs at low levels could be cultured, although they grew very slowly. 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. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. Clipboard, Search History, and several other advanced features are temporarily unavailable. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. 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. In 1998, Bodnar et al. Delayed effect: bulk telomeres decline to critical short length? Identification of a specific telomere terminal transferase activity in. DNA Southern blot experiments, done to examine the length of the telomeric DNA, showed that there was no bulk shortening of the telomeres. scientists may be able to stop cancer progression and potentially increase mortality. which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. Careers. Life extension is the concept of extending the human lifespan, either modestly through improvements in medicine or dramatically by increasing the maximum lifespan beyond its generally-settled limit of 125 years.. Several researchers in the area, along with "life extensionists", "immortalists" or "longevists" (those who wish to achieve longer lives themselves), postulate that future . 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 . 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. The unexpectedly rapid response to telomerase knockdown prompted us to carry out many controls to rule out possibilities such as targets other than the telomerase RNA being responsible for the effects on cell growth. Hence, the telomeric structure is continually being assembled and disassembled. The site is secure. Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. Note: Although not eating fish is better for your telomeres, eating fish isn't necessarily bad for you. . 2022 Sep;16(18):3380-3396. doi: 10.1002/1878-0261.13299. Telomerase is silenced in most normal cells but is active in an estimated 85% to 95% of human cancer cells. 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. PMC One of the telomerase-specific oncolytic adenovirus . 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). These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. -cancer cells show increased telomerase activity and the telomeres are not shortened. Lin J, Ly H, Hussain A, et al. MEK inhibition led to reduced TERT expression and telomerase activity. This site needs JavaScript to work properly. 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 . sharing sensitive information, make sure youre on a federal Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. This increased expression of telomerase makes it an attractive target for intervention. The significance of telomerase activation and cellular immortalization in human cancer. In collaboration with Jerry Cunha's lab at University of California, San Francisco, human bladder tumor cells were xenografted under the renal capsule in a mouse. -, Eisenberg DT. Disclaimer, National Library of Medicine Ashwagandha root extract increased telomerase activity with highest enhancement of ~45% at 10 - 50 g concentration. Wolkowitz OM, Mellon SH, Lindqvist D, Epel ES, Blackburn EH, Lin J, Reus VI, Burke H, Rosser R, Mahan L, Mackin S, Yang T, Weiner M, Mueller S. Psychiatry Res. Telomerase play a key role in the maintenance of telomere length and chromosome integrity. Telomerase inhibitor BIBR1532 increases sensitivities of Kras G12D and Kras G12V -Calu-3 cells, Figure 5. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Mutat Res. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. An example of mutated bases in the telomerase RNA and complementary mutant DNA bases incorporated into telomeric DNA (red A's and T's, respectively) through copying of the mutant telomerase template. Telomerase as a therapeutic target in glioblastoma. Cancer Sci. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Targeting. 8600 Rockville Pike 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. Drugs that inhibit telomerase activity, or kill telomerase-producing cells, may potentially stop and kill cancer cells in their tracks. The component of the telomerase ribonucleoprotein we targeted for knockdown by RNA interference (short interfering RNA or siRNA) was the telomerase RNA. Epub 2022 Jul 5. Therefore, Shang Li developed a short-term expression system for mutant-template telomerase RNA (6). Thomas Slaga . 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2022 Nov;12(11):319. doi: 10.1007/s13205-022-03373-2. Geron Corporation GERN, a late-stage clinical biopharmaceutical company, today highlighted multiple additions to its senior commercial leadership team, as it prepares for the potential . 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. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. A complex set of biological functions is encompassed in the word capping of the ends of the chromosomes. This was first shown in a model organism, the ciliate Tetrahymena, and subsequently in many other organisms. Activity per viable cell, measured at short hairpin RNA ( 6 ) telomerase-specific cytotoxic T-cells telomere. Age in humans is encrypted But there are risks aspect of these results was the rapidity of the telomerase... 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