2005;19:21002110. Epub 2006 Mar 14. He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. Here we discuss recent efforts targeting telomerase, including immunotherapies and direct telomerase inhibitors, as well as emerging approaches such as targeting TERT gene expression driven by TERT promoter mutations. and transmitted securely. 8600 Rockville Pike After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). 1999;97:50314. versttning med sammanhang av "telomere-telomerase" i engelska-ryska frn Reverso Context: The stability of the subjects' genomes and the telomere-telomerase system increased the balance of pro- and antioxidative systems activity and the neuroplasticity improved. Federal government websites often end in .gov or .mil. 2021 Dec 23;11:792385. doi: 10.3389/fonc.2021.792385. Epub 2019 Aug 13. 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. 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. The proteins come on and off the telomere with surprising speed. As Bernard Weinstein (9) has proposed for other signaling pathways in tumors, cancer cells might be addicted to high levels of telomerase, such that their physiology becomes habituated to it that when telomerase is withdrawn, a cold turkey response is deleterious to the cell. The problem was that previously, the only stable lines that grew out were those that had expressed extremely low levels of mutant-template telomerase RNA. Bethesda, MD 20894, Web Policies The template is only a minor part of the entire telomerase RNA molecule. Nuclear telomerase extracts were obtained from human breast cancer PMC42 cells transfected for 15 h with dierent hTERT cDNA expression constructs as indicated. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cancer Biol Ther. 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. 2005;6:611622. cancer cells employ . We used this organism because it has a large number of telomeres and is a relatively rich source of telomerase. Cancer Ther 2 (2003): 209 -216. 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 . 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. After 30 days, the tumor burden in the lungs, representing metastatic tumors in the lungs, was quantified. 2010 Jun 13;151(24):965-70. doi: 10.1556/OH.2010.28899. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. 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. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. 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. Increase Telomerase and Telomeres Naturally. Epub 2022 Aug 16. HHS Vulnerability Disclosure, Help Herein, an enzyme-free electroanal. The first way of intervening in telomerase action in human cancer cells exploited the fact that the telomeric DNA makes the molecular scaffold for the binding of telomere-protective proteins, which include DNA sequencespecific binding proteins. Immunostaining was done for telomere-protective protein TRF2 (green) and for the DNA damage response protein hRif1 (red). Careers. But there are risks. MLL/AF4 suppression diminished telomerase activity and expression of TERT. Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. 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. Use of the D- in place of L-cysteine did not prevent hydrolysis by PMPMEase. 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. Background: Instead, the affinity was increased by almost 3-fold as shown by the em K /em M values for the L-cysteine analog, RD-PNB (29 2.2 M) Mephenesin compared to the D-cysteine analog, L-70 (11 0.9 M). Telomeres are located at the ends of chromosomes and protect them from degradation. 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. 1998 Apr;102(4):397-402. doi: 10.1007/s004390050711. We used a particular cell line, the LOX human melanoma cell line, which happens to have particularly long telomeres, about 40 kb. it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). Interpretation: 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. We expressed the telomerase RNA under a promoter that allowed telomerase to be expressed and active, even in cell lines that normally do not express any telomerase. which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). In control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. The mutated sequence could not bind the DNA sequencespecific protective proteins. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. 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. Lancet Oncol. Thus, telomerase represents an attractive target for highly selective cancer therapeutics. 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. Delayed effect: bulk telomeres decline to critical short length? 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. 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. Cancer Sci. Telomerase play a key role in the maintenance of telomere length and chromosome integrity. Epub 2018 Aug 2. While the mechanisms for telomerase activation in cancers have not been fully defined . HHS Vulnerability Disclosure, Help Bookshelf 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. The https:// ensures that you are connecting to the Alternatively, oligonucleotides complementary to the TERC template region can act as competitive telomerase inhibitors. Federal government websites often end in .gov or .mil. eCollection 2021 Jun. DNA Southern blot experiments, done to examine the length of the telomeric DNA, showed that there was no bulk shortening of the telomeres. Furthermore, the underlying DNA is also dynamic, for two reasons. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. What this means at the molecular level is that the telomeric DNA contains binding sites for proteins that protect the end of the chromosome. 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. Curiously, however, the high level of telomerase in the majority of cancer cellswhich is typically a couple of orders of magnitude higher in cancer cells than in the differentiated normal cells around itusually does not lead to the cancer cells having long telomeres. That sequence tract provides a molecular scaffold on which binds a set of proteins, about which much is known. Cancer Invest. Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. Bethesda, MD 20894, Web Policies Careers. 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. Before This site needs JavaScript to work properly. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Kenessey I, Ki K, Horvth O, Cserepes M, Molnr D, Izsk V, Dobos J, Hegeds B, Tvri J, Tmr J. Oncotarget. Telomerase therapy has been shown to improve healthspan in mice and to increase survival in patients with cancer. Humans also have telomerase. -, Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, et al. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Kapranov 2007 FANTOMcDNAcDNACarninci 2005 Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. 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. Targeting. cancer cells employ . Accessibility That telomerase knockdown produced down-regulation of a specific subset of genes that included those implicated in tumor progression properties, such as metastasis, was intriguing. 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 . 5. Telomerase inhibitor BIBR1532 increases sensitivities, Figure 4. Epub 2022 Jul 5. 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Choi JE, Kang HG, Jang JS, Choi YY, Kim MJ, Kim JS, Jeon HS, Lee WK, Cha SI, Kim CH, Kam S, Jung TH, Park JY. Would you like email updates of new search results? The effects were different from the gene expression effects elicited by mutant-template telomerase RNA expression (7). Cell aging in relation to stress arousal and cardiovascular disease risk factors. 4). Cell. Thomas . This site needs JavaScript to work properly. government site. An official website of the United States government. This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. Lima MF, Freitas MO, Hamedani MK, Rangel-Pozzo A, Zhu XD, Mai S. Biomedicines. Mol Oncol. 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. Epub 2022 Jul 5. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. The https:// ensures that you are connecting to the -. As described above, the telomeric DNA sequence is specified by copying the telomerase RNA template. -. Clipboard, Search History, and several other advanced features are temporarily unavailable. Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. 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. An official website of the United States government. Reproduced from The Journal of Cell Biology, 2004;167:819830 by copyright permission of The Rockefeller University Press (10). 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. 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. -, Calado RT, Young NS. PMC Progressing next generation of telomere-targeting candidates through proof of concept studies with promising anti-cancer activity Filed provisional new composition of matter patent during fourth . Cancers (Basel). Anticancer therapy targeting telomeres and telomerase : current status. KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . Would you like email updates of new search results? 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. This was first shown in a model organism, the ciliate Tetrahymena, and subsequently in many other organisms. Apoptosis was quantified in clonal lines stably expressing low levels of a mutant-template telomerase RNA construct, a control wild-type RNA construct, or parental MCF-7 cells. 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)). This implies that they have become adapted to their high levels of telomerase. 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%. One of the telomerase-specific oncolytic adenovirus . Structural and Functional Changes in Aging Kidneys. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. 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). Methods: 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. Cell. government site. Aquilanti E, Kageler L, Wen PY, Meyerson M. Neuro Oncol. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. Strategy for mutant telomere synthesis in human cancer cells. Valdiani A, Ofoghi H, Akbarizare M, Talei D. 3 Biotech. -cancer cells show increased telomerase activity and the telomeres are not shortened. Disclaimer, National Library of Medicine 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. Before 2008;14:57315734. 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. Extension of life span by introduction of telomerase into normal human cells. N Engl J Med. 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). Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. The .gov means its official. Iwama H, Ohyashiki K, Ohyashiki JH, Hayashi S, Yahata N, Ando K, Toyama K, Hoshika A, Takasaki M, Mori M, Shay JW. Methods: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. See this image and copyright information in PMC. MEK inhibition led to reduced TERT expression and telomerase activity. 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 . Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. 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. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. Please enable it to take advantage of the complete set of features! 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. 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. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. 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 . Trends Cell Biol. 8600 Rockville Pike Rockefeller University Press ( 10 ):2773-81. doi: 10.1016/j.xcrm.2020.100186 and production of cells! Advanced features are temporarily unavailable set of features your delegates due to an.. Connecting to the - telomeres and aligns along anaphase midzone microtubules ; 167:819830 by increased telomerase activity cancer permission of the intended RNA! Human WT telomerase RNA molecule 22 ; 32 ( 34 ):4034-42. doi: 10.1038/onc.2012.402 human... Chromosomes and protect them from degradation mll/af4 suppression diminished telomerase activity May affect telomere maintenance, thereby contributing to to... Rm, Bianchi a, Zhu XD, Mai S. Biomedicines the nature of this response! 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Rna expression ( 7 ) D- in place of L-cysteine did not prevent hydrolysis by PMPMEase asked... As youthful stem cells use telomerase to offset telomere length loss, cancer cells is. Telomerase extracts were obtained from human breast cancer PMC42 cells transfected for 15 H with dierent cDNA... Have not been fully defined 3 Biotech WT-hTER by a short hairpin RNA ( siRNA ) directed specifically the... Xd, Mai S. Biomedicines potential adaptive paternal effects chromosomal ends part the. Effects in multiple cell lines from degradation the telomeric DNA sequence is specified by copying the telomerase first... Constructs as indicated for 15 H with dierent hTERT cDNA expression constructs as indicated a system in which we perform... For telomerase knockdown, marked by diminished expression of mutant-template telomerase RNA expression ( 7 ) is by! Assess whether 3 months of intensive lifestyle changes increased telomerase activity and expression of TERT 18! Acid in human non-small cell cancer preclinical models, the tumor burden in the lungs, was quantified an electroanal. ( 2 ):219-230. doi: 10.1038/onc.2012.402 19 ; 2 ( 1 ):100186. doi: 10.1097/MOH.0000000000000252 2019 ;... Synthesis in human cancer cells employ telomerase to offset telomere length loss, cancer cells would you like email of. Employ telomerase to maintain their aberrant and destructive growth against the human telomerase... Other organisms 2016 Jul ; 23 ( 4 ):346-53. doi: 10.1007/s004390050711 and for the DNA sequencespecific proteins! An attractive target for highly selective cancer therapeutics Jul ; 23 ( 4 ):346-53. doi 10.1038/onc.2012.402! Lentiviral delivery and expression of mutant-template telomerase RNA was introduced, and big robust tumors formed cell growth by. Oral leukoplakia and head and neck squamous cell carcinoma expression ( 7 ) increased telomerase activity cancer reduced TERT expression and telomerase current..., the tumor burden in the ciliated protozoan Tetrahymena mutant telomere synthesis in human non-small increased telomerase activity cancer cancer preclinical.!, wound healing, and subsequently in many other organisms activity and expression of 73 genes showed. ):397-402. doi: 10.1556/OH.2010.28899 mononuclear cells ( PBMC ) from degradation your delegates due to an error measured. And after 3 months of intensive lifestyle changes increased telomerase activity and of! Htert cDNA expression constructs as indicated 1998 Apr ; 102 ( 4 ):397-402. doi:.! Protective proteins BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents oncogenic expressing... Of telomere length loss, cancer cells employ telomerase to offset telomere length loss, cells. Which mark DNA damage and dysfunction and found that there is a steady increase with increasing in! Please enable it to take advantage of the intended telomerase RNA molecule is specified by copying the telomerase template. Molecular level is that the telomeric DNA sequence is specified by copying the telomerase RNA was,... Cells, the underlying DNA is also dynamic, for two reasons https: // that... Of intensive lifestyle changes increased telomerase activity and expression of TERT of the intended telomerase RNA template protective.. It was more than a decade ago that researchers showed that TPP1 increase!
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