3). That sequence tract provides a molecular scaffold on which binds a set of proteins, about which much is known. Haploinsufficiency of hTERT leads to telomere dysfunction and radiosensitivity in human cancer cells. 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%. Identification of a specific telomere terminal transferase activity in. 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. 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be addicted to high levels of telomerase, such that their physiology becomes habituated to it that when telomerase is withdrawn, a cold turkey response is deleterious to the cell. -. Trends Cell Biol. Aggregation-induced emission luminogens reveal cell cycle-dependent telomerase activity in cancer cells. 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. Epub 2013 May 5. The siRNA was directed against either the wild-type template sequence or the conserved pseudoknot structure of human telomerase RNA. Would you like email updates of new search results? One of the telomerase-specific oncolytic adenovirus . 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. Which of the following statements is accurate about the activity of the telomerase enzyme in cancer cells? Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Recently a germline alteration of telomere-telomerase complex has been identified in patients with familial pap-illary thyroid cancer, characterized by short telomeres and increased expression and activity of telomerase compared to patients with sporadic papillary thyroid cancer. official website and that any information you provide is encrypted 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. Bookshelf which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. MeSH Therefore, Shang Li developed a short-term expression system for mutant-template telomerase RNA (6). Valdiani A, Ofoghi H, Akbarizare M, Talei D. 3 Biotech. 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. In addition, higher TERT expression was seen in Kras-mutant NSCLC than that with wild-type Kras. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. sharing sensitive information, make sure youre on a federal 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. Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. is the main cause for wide range of age-associated diseases like cancer, ischemic heart disease, stroke, type 2 diabetes, neurodegenerative diseases . Thus, telomerase represents an attractive target for highly selective cancer therapeutics. 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. Kim MM, Rivera MA, Botchkina IL, Shalaby R, Thor AD, Blackburn EH. Cancer research, 1995. 4. Thomas Slaga . Telomerase is commonly expressed in human cancer cells. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. 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!". Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. 2019 Nov 15;105(4):861-874. doi: 10.1016/j.ijrobp.2019.08.009. In humans, telomerase enzyme activity is absent in most normal cells but present in the majority of tumors (4). 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. Resulting in the overall . Telomerase play a key role in the maintenance of telomere length and chromosome integrity. Cell aging in relation to stress arousal and cardiovascular disease risk factors. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. Mol. We investigated the effect of telomerase inhibition on cancer cells using two different approaches. We also showed that a kind of DNA damage response was elicited, as might be predicted because the telomeres were expected to become uncapped. 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. Teloxantron inhibits the processivity of telomerase with preferential DNA damage on telomeres. -, Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. 24 patients had sufficient PBMCs needed for longitudinal analysis. Clipboard, Search History, and several other advanced features are temporarily unavailable. Curr Opin Hematol. J. Mol. While the mechanisms for telomerase activation in cancers have not been fully defined, they include telomerase catalytic subunit gene (hTERT) amplification and trans-activation of the hTERT promoter by the myc oncogene product. US11007255B2 - Cancer vaccines and methods of treatment using the same - Google Patents . Herein, an enzyme-free electroanal. This study was published in the prestigious . The site is secure. The fruit fly Drosophila melanogaster . Psychoneuroendocrinology. Tsirpanlis G, Chatzipanagiotou S, Boufidou F, Kordinas V, Alevyzaki F, Zoga M, Kyritsis I, Stamatelou K, Triantafyllis G, Nicolaou C. Am J Nephrol. K01AT004199/AT/NCCIH NIH HHS/United States. Antitumor activity of systemically delivered ribozymes targeting murine telomerase RNA. 1994;266:20115. Clin Cancer Res. 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. Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin's Lymphoma Cell Death. levels of TERT or telomerase activity (Fu et al., 2000). Keywords: The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. Clipboard, Search History, and several other advanced features are temporarily unavailable. Hiyama, E; Yokoyama, T; Tatsumoto, N; Hiyama, K; Imamura, Y; Murakami, Y; Kodama, T; Piatyszek, M A; Shay, J W . 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). Mammalian telomeres end in a large duplex loop. 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). Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Cell. The human telomerase RNA, a non-mRNA, can be efficiently knocked down by expression of a short hairpin RNA from a lentiviral construct. 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). This inactive complex swamps out the endogenous telomerase. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. After 30 days, the tumor burden in the lungs, representing metastatic tumors in the lungs, was quantified. Although the mouse telomerase RNA component levels were increased 2-fold and correlated well with proliferation markers, activity levels were increased 10-fold, suggesting a second level of regulation in addition to growth regulation . Epub 2022 Jul 15. Clipboard, Search History, and several other advanced features are temporarily unavailable. Epub 2022 Jul 5. Curr Opin Genet Dev. The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. 2011;23:149167. 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. HHS Vulnerability Disclosure, Help 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. An increase in telomerase activity in one context could be viewed as beneficial because it might lead to an increase in relative telomere length . Telomere end-replication problem and cell aging. FOIA Would you like email updates of new search results? An official website of the United States government. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH 2007;21(6):375-85. doi: 10.2165/00063030-200721060-00005. Epub 2018 Aug 2. Dybiec J, Szlagor M, Mynarska E, Rysz J, Franczyk B. Int J Mol Sci. Too much telomerase can help confer immortality onto cancer cells and actually increase the likelihood of cancer, . Proc Am Thorac Soc. 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. Figure 1. The team discovered that BRG1 and TPP1 interact to promote TERT-driven telomerase activity. Telomerase inhibitor BIBR1532 shortens telomere length and suppresses mutant Kras-induced cell long-term proliferation, Figure 3. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. Clin Lung Cancer. Thus, the RNA and the protein of telomerase collaborate in the enzymatic action. -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. It is in that latter context that we are interested in intervening in telomerase action. We did these experiments in a manner that made the test of the effects as stringent as possible because we did not include a drug selection step after infecting the cells with the lentiviral vectors. At various levels, it is also active in other adult human cells, but the levels are often very low and not enough to sustain telomere length over a lifetime. Effect is immediate*as fast as can be measured. 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. Telomerase and the benefits of healthy living. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. 2022 Oct 30;10(11):2755. doi: 10.3390/biomedicines10112755. . 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. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. -cancer cells show decreased telomerase activity and the telomeres are shortened. cancer cells employ . 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. Telomerase inhibitor BIBR1532 increases sensitivities, Figure 4. 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