This study is registered on the ClinicalTrials.gov website, number NCT00739791. Increased telomerase activity was associated with a decrease in the level of low-density lipoprotein cholesterol (LDL) and a decrease . Extension of life span by introduction of telomerase into normal human cells. A complex set of biological functions is encompassed in the word capping of the ends of the chromosomes. Lin J, Ly H, Hussain A, et al. 2009;361:23532365. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. One of the telomerase-specific oncolytic adenovirus . Telomerase activity can immortalize cancer cells and about 90% of cancers are characterized by increased telomere activity. 2015;65:87108. Copyright 2022 by the American Association for Cancer Research. Similar to astragalus, extracts of cycloastragenol can increase telomerase activity. Telomerase activity in peripheral blood mononuclear cells was measured by a PCR-designed telomeric repeat amplification protocol in 63 lung cancer patients and 190 healthy controls that were matched for age, gender, and smoking status. 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. Unable to load your collection due to an error, Unable to load your delegates due to an error. We found that the cellular response to this way of uncapping of telomeres in cancer cells was a very robust apoptotic response (Fig. As mentioned previously, if telomerase is present in sufficient amounts, it permits cells to keep multiplying. See this image and copyright information in PMC. Epub 2020 Feb 27. 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 . To detect telomerase, a novel surface-enhanced Raman scattering (SERS) biosensor was constructed using the dual DNA-catalyzed amplification strategy composed of strand displacement amplification (SDA . 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. For this reason, some have called telomerase the "immortality enzyme." Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. Ding X, Cheng J, Pang Q, Wei X, Zhang X, Wang P, Yuan Z, Qian D. Int J Radiat Oncol Biol Phys. -, Morrison SJ, Prowse KR, Ho P, Weissman IL. 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. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Researchers found that the enzyme telomerase, which is active in most tumor cells, may also protect healthy adult cells from becoming cancerous. cancer cells employ . Urol Oncol. 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. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. CA: A Cancer Journal for Clinicians. -. Thomas Slaga . is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . 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. 2022 Oct 30;10(11):2755. doi: 10.3390/biomedicines10112755. Epub 2022 Oct 10. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH The RNA has a short template sequence that is copied into DNA, which extends, and thus lengthens, the chromosomal DNA. Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. Kapranov 2007 FANTOMcDNAcDNACarninci 2005 Telomerase activity analysis was . 2011;23:149167. Epub 2022 Sep 14. Would you like email updates of new search results? 2006;26(1):91-6. doi: 10.1159/000092031. 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). 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. Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin's Lymphoma Cell Death. 2022 Dec 6;23(23):15435. doi: 10.3390/ijms232315435. Nuclear telomerase extracts were obtained from human breast cancer PMC42 cells transfected for 15 h with dierent hTERT cDNA expression constructs as indicated. 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. Kras mutations upregulate TERT expression and telomerase activities by the RAS-MEK pathway, Figure 2. Exp Cell Res. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. Please enable it to take advantage of the complete set of features! Clipboard, Search History, and several other advanced features are temporarily unavailable. Would you like email updates of new search results? In 1998, Bodnar et al. 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. Telomerase is commonly expressed in human cancer cells. Mol Cancer Res (2005) 3 (9): 477-482. The https:// ensures that you are connecting to the eCollection 2021 Jun. 2000 Jan;462(1):31-47. doi: 10.1016/s1383-5742(99)00091-5. 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. 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). Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. Diminished telomerase activity by MMPL resulted in the suppression of both telomerase . official website and that any information you provide is encrypted Telomeres are located at the ends of chromosomes and protect them from degradation. Strategy for mutant telomere synthesis in human cancer cells. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). 4. 8600 Rockville Pike Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . An increase in telomerase activity in one context could be viewed as beneficial because it might lead to an increase in relative telomere length . Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. Keywords: FOIA Telomerase activity in hematopoietic cells is associated with self-renewal potential. The component of the telomerase ribonucleoprotein we targeted for knockdown by RNA interference (short interfering RNA or siRNA) was the telomerase RNA. 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. 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). Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. 2022 Oct 26;14(21):5257. doi: 10.3390/cancers14215257. Ovals and diamonds, sequence-specific DNA binding proteins that protect telomeric DNA and cap it; red, telomerase; blue Xs, mutated telomerase RNA template and correspondingly mutated telomeric DNA sequence. Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. 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. 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. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. Targeting the "hallmarks of aging" to slow aging and treat age-related disease: fact or fiction? -cancer cells show decreased telomerase activity and the telomeres are shortened. HHS Vulnerability Disclosure, Help 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. The proteins come on and off the telomere with surprising speed. 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). The https:// ensures that you are connecting to the . 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. Anticancer therapy targeting telomeres and telomerase : current status. PMC Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. The population of cells stably expressing the various different mutant-template RNAs at low levels could be cultured, although they grew very slowly. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. This study was published in the prestigious . 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. (7)]. Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. 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. 13. PMC Bookshelf 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. Telomeres, telomerase, and myc. -, Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, . The p53 response pathway is commonly abrogated in human cancers. Accessibility MEK inhibition led to reduced TERT expression and telomerase activity. 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)). FOIA 4). 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 . Use of the D- in place of L-cysteine did not prevent hydrolysis by PMPMEase. Liu Y, Betori RC, Pagacz J, Frost GB, Efimova EV, Wu D, Wolfgeher DJ, Bryan TM, Cohen SB, Scheidt KA, Kron SJ. The regulation of telomerase activity in human cells plays a significant role in the development of cancer. 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. Careers. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Finally, we observed the same kinds of rapid growth inhibitory effects in the context of a more in vivolike setting for tumor cells. Delay dependent on initial telomere length in the cancer cells? The number of papillomas showing higher levels of telomerase activity increased at 20 weeks, and at 30 weeks of promotion, 100% of papillomas expressed significantly higher levels of telomerase. Federal government websites often end in .gov or .mil. HHS Vulnerability Disclosure, Help 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. MLL/AF4 suppression diminished telomerase activity and expression of TERT. 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. Immunotherapies, MeSH Mammalian telomeres end in a large duplex loop. An official website of the United States government. The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures. The ribozyme treatment decreased the metastatic burden. The site is secure. The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Remember, this enzyme isn't found in . Ornish D, Lin J, Chan JM, Epel E, Kemp C, Weidner G, Marlin R, Frenda SJ, Magbanua MJM, Daubenmier J, Estay I, Hills NK, Chainani-Wu N, Carroll PR, Blackburn EH. . Telomerase play a key role in the maintenance of telomere length and chromosome integrity. Mutat Res. Nat Rev Genet. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. Published in the November 2008 issue of Lancet Oncology, Dr. Dean Ornish's latest research, a pilot study on the effects of dietary and lifestyle changes in 30 men with low risk prostate cancer, suggests the answer is a resounding "Yes!". Bethesda, MD 20894, Web Policies In chronic lymphocytic leukemia cells, increased activity of the hypoxic pathway and ATM locus defects can render wild-type p53 hypophosphorylated. 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 2022 Jul 15. Hence, the telomeric structure is continually being assembled and disassembled. Kras mutations; chemoresistance; lung cancer; telomerase; telomere. We are very interested in understanding the signaling pathways leading to the apoptosis, which is under active investigation right now. What this means at the molecular level is that the telomeric DNA contains binding sites for proteins that protect the end of the chromosome. Bookshelf 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 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. Another study from the same group further clarified this potential link between telomerase expression and myofibroblast differentiation (18); using the same bleomycin-induced pulmonary fibrosis rat model, they demonstrated that the inhibition of fibroblast telomerase activity led to increased -SMA expression, which represents a marker of . An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. Telomerase has been considered as a biomarker for early diagnosis and prognosis assessment of hepatocellular carcinoma (HCC), while the highly sensitive and specific methods remain challenging. 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). In all cases, we obtained a surprising result: rapid inhibition of the growth of human telomerase-positive cancer cells. 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. Telomerase activity in gastric cancer. Before The rapid inhibition of cell growth seen on knockdown of telomerase indicated that cancer cells are particularly susceptible to its depletion. 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. Nat Rev Cancer. Please enable it to take advantage of the complete set of features! Prospects for anti-neoplastic therapies based on telomere biology. BioDrugs. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. While the mechanisms for telomerase activation in cancers have not been fully defined . -cancer cells show increased telomerase activity and the telomeres are not shortened. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . Unable to load your collection due to an error, Unable to load your delegates due to an error. Telomerase is tightly repressed in the vast majority of normal human somatic cells but becomes activated during cellular immortalization and in cancers. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. eCollection 2021. Due to telomerase inhibition, activity, or expression, these drugs might kill tumor cells by allowing . doi: 10.1016/j.chembiol.2022.09.002. Larger randomised controlled trials are warranted to confirm the findings of . Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. 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. -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. These proteins include DNA sequencespecific binding proteins and other proteins that together, in effect, sheathe the chromosome end. However, development of telomerase inhibitors . 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. Epub 2013 Sep 17. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, R01CA226888/U.S. Weinstein IB. Findings: official website and that any information you provide is encrypted That sequence tract provides a molecular scaffold on which binds a set of proteins, about which much is known. Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization. -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Tumor cells in control . Please enable it to take advantage of the complete set of features! strategy was developed for reliable and highly sensitive telomerase activity assay based on the increased electrochem. (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. 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. Telomere end-replication problem and cell aging. Epub 2018 Aug 2. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. 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. -, de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. Hence, such a p53-independent apoptotic response is desirable if one is interested in intervening in telomerase action as an anticancer approach. Bookshelf Accessibility Telomerase inhibitor BIBR1532 inhibits Kras, Figure 3. For example, up-regulation of p21 expression was seen, consistent with a DNA damage response. 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. Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. The https:// ensures that you are connecting to the 8600 Rockville Pike 2018 Dec 1;24(23):5963-5976. doi: 10.1158/1078-0432.CCR-18-0876. 3. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; And, indeed, many labs and many groups have now shown that the apparent increase in telomerase is a common feature of human tumor cells. Epub 2012 Sep 10. 2022 Sep;22(9):515-532. doi: 10.1038/s41568-022-00490-1. The human telomerase RNA, a non-mRNA, can be efficiently knocked down by expression of a short hairpin RNA from a lentiviral construct. official website and that any information you provide is encrypted Hence, the DNA at the ends of the chromosomes was effectively naked. 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. Cell Chem Biol. 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. Understanding Ras: it ain't over 'til it's over. Thomas . Epub 2006 Mar 14. 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. Mutagenesis. The tumors that expressed the mutant-template telomerase RNA were smaller and much less vascularized, and the tumors weighed less (6). DNA methylation of the TERT promoter and its impact on human cancer. 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 . Recent studies also suggest that telomerase is implicated in tumor progression in unexpected ways. Various lines of evidence showed that the cells that grew out were those that either did not receive the lentivector or failed to overexpress the mutant-template telomerase RNA. Telomerase and the benefits of healthy living. Within a few days, the cell growth rate was markedly decreased. 1994;266:20115. The "Telomere Erosion in Disposable Soma" theory proposes that replicative loss of telomeric DNA provided a selective advantage during evolution that allowed lifespan to increase by supressing cancer before reproduction (). 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)). The authors declare that they have no conflict of interest. Thus, there exists a puzzle that the abundant telomerase activity is apparently not there to make long telomeres. Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Gupta N, Patel HD, Taylor J, Borin JF, Jacobsohn K, Kenfield SA, Eggener SE, Price C, Davuluri M, Byrne N, Bivalacqua TJ, Loeb S. Prostate Cancer Prostatic Dis. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and Telomerase inhibitor BIBR1532 prevents Kras G12D -Calu-3 xenograft tumor growth and increases the, Figure 6. 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. Telomeres and human disease: aging, cancer and beyond. Clipboard, Search History, and several other advanced features are temporarily unavailable. Encouragingly, this is effective even with very low levels of expression of the mutant-template RNAs. This site needs JavaScript to work properly. NOTE: Comparison of human cancer cell growth inhibitory effects predicted and observed when telomerase enzymatic activity was only inhibited (Old) versus those observed in cells in which total telomerase RNA levels were knocked down (New). 1999;97:527538. 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. Liutkeviciene R, Mikalauskaite R, Gedvilaite G, Glebauskiene B, Kriauciuniene L, emaitien R. Medicina (Kaunas). MeSH 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. . Targeting. Even people living in the Blue Zones eat fish in moderation. The template is only a minor part of the entire telomerase RNA molecule. 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. Psychoneuroendocrinology.

Carlos Ponce Children, Yellowstone County Jail Roster, Phil Read Wife Madeleine Read, Articles I