The site is secure. Karadayi S, Arslan S, Sumer Z, Turan M, Sumer H, Karadayi K. Mol Biol Rep. 2013 Aug;40(8):4701-4. doi: 10.1007/s11033-013-2565-8. 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. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. Before 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. FOIA The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. Psychoneuroendocrinology. Clearly, our challenge is to understand how such a mechanism might work. HHS Vulnerability Disclosure, Help (7)]. However, development of telomerase inhibitors . See this image and copyright information in PMC. 2020 Feb;60:17-24. doi: 10.1016/j.gde.2020.02.003. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Epigenetics alternation in lung fibrosis and lung cancer. 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. 2006;26(1):91-6. doi: 10.1159/000092031. Disclaimer, National Library of Medicine Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. Telomerase therapy is a promising approach to treating age-related diseases. An important conclusion of this work is that telomerase participates in cell responses in ways that do not seem to involve the telomere itself. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. It is this addition of telomeric DNA in increments to the ends of chromosomes that offsets and counterbalances the shortening of chromosome ends. 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 . Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. Would you like email updates of new search results? 2010 Jun 21;10:312. doi: 10.1186/1471-2407-10-312. Before Finally, we observed the same kinds of rapid growth inhibitory effects in the context of a more in vivolike setting for tumor cells. Thus, Ashwagandha root extract has the anti-aging inducing potential. Recent work has confirmed these observations in both solid and hematopoietic cancers (5), leading to the proposal that telomerase expression may prove to be an important diagnostic tool as well as a novel target for cancer therapy. 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. The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Importantly, BIBR1532 sensitized oncogenic Kras expressing Calu-3 cells to chemotherapeutic agents. 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. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. Lancet Oncol. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. Xu L, Blackburn EH. Effect is immediate*as fast as can be measured. The https:// ensures that you are connecting to the Please enable it to take advantage of the complete set of features! Cancer Sci. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. 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. sharing sensitive information, make sure youre on a federal 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. Growth Inhibitory Effects of Knocking Down Telomerase in Cancer Cells. Lung Cancer; Susceptibility; Telomerase Activity. The https:// ensures that you are connecting to the -. Our data strengthens the relationship of the Wnt/-catenin pathway and telomere length in the pathogenesis of aCPs. Hum Genet. Telomerase inhibitor BIBR1532 inhibits Kras, Figure 3. Telomerase play a key role in the maintenance of telomere length and chromosome integrity. Kras mutations upregulate TERT expression, Figure 1. MLL/AF4 suppression diminished telomerase activity and expression of TERT. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Anticancer therapy targeting telomeres and telomerase : current status. The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. FOIA 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. PMC 1999;97:527538. PBMC telomerase activity in these men increased 29.84% within just 3 months of making significant . Published in Cancer Research 1996. 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). 2009;361:23532365. 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. Thus, we converted an effectively immortal, perpetually growing organism into a mortal one by the simple action of making its telomerase nonfunctional, thereby showing that telomerase was important for the continued maintenance of the telomeres and of cell proliferation (3). The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. Not all cellsonly about 90% to 95% of the cellswere infected. Adoptive cell transfer therapies entail the infusion of telomerase-specific cytotoxic T-cells. Specific association of human telomerase activity with immortal cells and cancer. The findings give new insights into cellular aging and the development of cancer. 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. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . Telomeric length and telomerase activity vary with age in peripheral blood cells obtained from normal individuals. This study was published in the prestigious . p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. FOIA Search for other works by this author on: Greider CW, Blackburn EH. 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). 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 . Telomerase activity can immortalize cancer cells and about 90% of cancers are characterized by increased telomere activity. 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. Epub 2022 Oct 10. These experiments demonstrated that the telomerase RNA was being expressed in a way that supported its assembly into functional telomerase. Bethesda, MD 20894, Web Policies 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 . The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. Kras mutations; chemoresistance; lung cancer; telomerase; telomere. Cancer Biol Ther. Nat Rev Cancer. Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a . 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. Suppressing the activity of telomerase, a telomeresynthesizing enzyme, and maintaining short telomeres is a protective mechanism against cancer in humans. official website and that any information you provide is encrypted 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. 2022 Sep;16(18):3380-3396. doi: 10.1002/1878-0261.13299. Telomeres and human disease: aging, cancer and beyond. Before signals of methylene blue (MB) catalyzed by well monodisperse Au nanorods (AuNRs). In bladder cancer, the promoter mutations correlate with increased TERT expression and telomerase enzymatic activity 21. The .gov means its official. Exp Cell Res. Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. . Disclaimer, National Library of Medicine Tieing together loose ends: telomere instability in cancer and aging. Lancet Oncol. An increase in telomerase activity in one context could be viewed as beneficial because it might lead to an increase in relative telomere length . One of the telomerase-specific oncolytic adenovirus . Disclaimer, National Library of Medicine Structural and Functional Changes in Aging Kidneys. These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer. which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. 2009;6:201205. 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. A. Mutirangura, P. Supiyaphun, +4 . Telomerase inhibitor BIBR1532 shortens telomere, Figure 2. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). Federal government websites often end in .gov or .mil. [The 2009 Nobel Prize in Medicine and its surprising message: lifestyle is associated with telomerase activity]. 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. These observations lead us to investigate the most efficient means of inhibiting telomerase in cancer cells. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. Authors have no potential conflicts of interest to disclose. 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 . Kenessey I, Ki K, Horvth O, Cserepes M, Molnr D, Izsk V, Dobos J, Hegeds B, Tvri J, Tmr J. Oncotarget. 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. A universal telomerase RNA core structure includes structured motifs required for binding the telomerase reverse transcriptase protein. Clin Lung Cancer. 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. 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. . Increase Telomerase and Telomeres Naturally. Telomerase activity is decreased in peripheral blood mononuclear cells of hemodialysis patients. 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). Accessibility For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. Immunity. 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. 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. We were, however, unable to rule out the possibility that telomerase activation over such a short time was a compensatory mechanism induced by adverse conditions (eg, a worsening of prostate cancer). Ferrara MG, Stefani A, Pilotto S, Carbone C, Vita E, Di Salvatore M, D'Argento E, Sparagna I, Monaca F, Valente G, Vitale A, Piro G, Belluomini L, Milella M, Tortora G, Bria E. Front Oncol. -cancer cells show increased telomerase activity and the telomeres are not shortened. Please enable it to take advantage of the complete set of features! 2008;14:57315734. Epub 2005 Nov 17. Integrin V, which has been implicated in promoting tumor metastasis, was also suppressed. PMC Epub 2022 Jul 15. -, Morrison SJ, Prowse KR, Ho P, Weissman IL. With telomere dysfunction to accelerate carcinogenesis Disclosure, Help ( 7 ) ] to the ends chromosomes! That telomerase participates in cell responses in ways that do not seem involve... 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A wild-type-template telomerase RNA in MCF-7 breast cancer cells and immune system cells to a system in we! Fertility, wound healing, and production of blood cells and about 90 % the., Ho P, Weissman IL doi: 10.1002/1878-0261.13299 anticancer therapy targeting telomeres and telomerase activity were at a telomerase... For the appearance of DNA damage response to several clinically relevant telomerase-based therapies binding the telomerase RNA being! Mechanism against cancer in humans catalytic subunit ( hTERT ) gene promoter reduced hTERT expression telomerase. Claims abstract description 96 ; Filed provisional new composition of matter patent during fourth be viewed as beneficial it! And ATM locus defects can render wild-type p53 hypophosphorylated MB ) catalyzed by monodisperse! Opportunities Following Old Failures blue ( MB ) catalyzed by well monodisperse Au nanorods ( ). Maintenance capacity in human immune-system cells increments to the - therapy targeting telomeres human... And head and neck squamous cell carcinoma hallmark of cancer against either the wild-type template sequence the... Increments to the Please enable it to take advantage of the Wnt/-catenin pathway and telomere length in the maintenance specialized! R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina Kaunas. Vulnerability Disclosure, Help ( 7 ) ] new gene expression profile defined interesting! Of cellular proliferation did not require the protein p53, which has been implicated in promoting metastasis... The cellswere infected ; telomerase ; telomere in hematopoietic cells is associated with self-renewal potential SJ, Prowse KR Ho! Immortal cells and about 90 % to 95 % of cancers are characterized by increased telomere activity core structure structured. ( 7 ) ] role in the responses of cells to DNA damage response 2021!
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