This site needs JavaScript to work properly. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, P50 CA174523/CA/NCI NIH HHS/United States, P50CA174523/U.S. . The site is secure. -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. 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. Jang JS, Choi YY, Lee WK, Choi JE, Cha SI, Kim YJ, Kim CH, Kam S, Jung TH, Park JY. Hence, the telomeric structure is continually being assembled and disassembled. Influences of Long-Term Exercise and High-Fat Diet on Age-Related Telomere Shortening in Rats. An evolutionary review of human telomere biology: the thrifty telomere hypothesis and notes on potential adaptive paternal effects. The template is only a minor part of the entire telomerase RNA molecule. Telomerase levels are very highly regulated in normal human cells. Just as youthful stem cells use telomerase to offset telomere length loss, cancer cells employ telomerase to maintain their aberrant and destructive growth. Interestingly, Zhang et al. 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. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. These cancer cells already had high levels of telomerase, including high levels of the normal wild-type telomerase RNA. 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. Please enable it to take advantage of the complete set of features! One reason is that, as was predicted in the 1970s, the known mechanism of DNA polymerase prevents complete DNA replication all the way to the ends of the chromosome at every round of replication. Suspi- M.P. The telomeres consist, first, of a DNA scaffold composed of a tract of very simple repeated DNA sequences. "Inhibition of Telomerase activity in human cancer cells by RNA interference". See this image and copyright information in PMC. He X, Qiao Q, Ge N, Nan J, Shen S, Wang Z, Yang Y, Bao G. BMC Cancer. 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 . Telomerase inhibitor BIBR1532 increases sensitivities of Kras G12D and Kras G12V -Calu-3 cells, Figure 5. FOIA Incorporation of nucleoside analogues into newly synthesized telomeres impairs POT1 binding, causing telomere dysfunction that elicits a DNA damage response and cell death. At a Glance. DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . Although much work remains to be done, effective strategies targeting telomerase will have a transformative impact for cancer therapy and the prospect of clinically effective drugs is boosted by recent advances in structural models of human telomerase. Clipboard, Search History, and several other advanced features are temporarily unavailable. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. -, Morrison SJ, Prowse KR, Ho P, Weissman IL. 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 . Larger randomised controlled trials are warranted to confirm the findings of this study. 2023 Jan;28(1):242-255. doi: 10.1038/s41380-022-01680-x. . Given this nding and the pilot nature of this study, we report . HHS Vulnerability Disclosure, Help 2007 Apr-May;25(3):197-208. doi: 10.1080/07357900701208683. 2002 Nov;17(6):539-50. doi: 10.1093/mutage/17.6.539. 24 patients had sufficient PBMCs needed for longitudinal analysis. Telomeres are located at the ends of chromosomes and protect them from degradation. We observed that at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of telomerase activity. Cynthia Marcelo. The fruit fly Drosophila melanogaster . The .gov means its official. Lancet Oncol. 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. eCollection 2021 Jun. Bethesda, MD 20894, Web Policies Thus, again, no evidence was found for any resistant subpopulation of cells that evade the effect of mutant-template telomerase RNA expression. 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. . Once again, the effects did not require p53 (7). -, Calado RT, Young NS. Telomerase has long been considered as a biomarker for cancer diagnosis and a therapeutic target for drug discovery. Telomerase activity in hematopoietic cells is associated with self-renewal potential. Unable to load your collection due to an error, Unable to load your delegates due to an error. Telomerase therapy is a promising approach to treating age-related diseases. https://doi.org/10.1158/1541-7786.MCR-05-0147. After much study, it has emerged that the RNAs from evolutionarily diverse eukaryotes share a common core structure (2). As mentioned previously, if telomerase is present in sufficient amounts, it permits cells to keep multiplying. We used a particular cell line, the LOX human melanoma cell line, which happens to have particularly long telomeres, about 40 kb. However, development of telomerase inhibitors has been challenging and thus far there are no clinically approved strategies exploiting this cancer target. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. PMC Blocking telomerase could impair fertility, wound healing, and production of blood cells and immune system cells. Also, Ground flax and chia seeds are excellent vegan sources of short-chain (ALA) omega-3s. Lung Cancer; Susceptibility; Telomerase Activity. Careers. 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). The rapid response of telomerase-positive cancer cells to an abrupt depletion of their telomerase despite the lack of telomere uncapping prompted the hypothesis that these effects were unrelated to telomere maintenance or telomere function. Telomeres and human disease: aging, cancer and beyond. Telomerase reactivation causes aggressive cancer Third- and fourth-generation mice with telomerase activated by 4-OHT had a median survival of 30 days and more frequent tumor infiltration to the spleen, kidney, liver, lung, bone marrow and brain than did control-treated mice, 70 percent of which lived beyond 50 days. Cell Chem Biol. The mutated sequence could not bind the DNA sequencespecific protective proteins. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. Wu X, Wu J, Dai J, Chen B, Chen Z, Wang S, Wu F, Lou X, Xia F. Natl Sci Rev. 1996;5:20716. Tornesello ML, Cerasuolo A, Starita N, Tornesello AL, Bonelli P, Tuccillo FM, Buonaguro L, Isaguliants MG, Buonaguro FM. 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. FOIA Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. 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). and transmitted securely. 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. 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. 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). Accessibility 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). For these immunostaining experiments, we used proteins that are known to accumulate in DNA damage foci at sites of DNA damage, such as the protein hRif1. doi: 10.1093/nsr/nwaa306. Yet that small fraction of the total telomerase that contained the mutant-template telomerase RNA was sufficient to elicit a robust apoptotic response. One of the telomerase-specific oncolytic adenovirus . The proteins come on and off the telomere with surprising speed. Herein, an enzyme-free electroanal. tumours. / Critical Re6iews in Oncology/Hematology 41 (2002) 29-40 37 cious cytogenetic abnormalities in breast cancer corre- with telomerase activity were ultimately diagnosed as late with increased telomerase activity, namely 3q+ carcinoma and 6/7 without telomerase activity were (site of hTR), 8q+ (c-myc), and 17p (p53 . Biol 1992;225:95160. -cancer cells show increased telomerase activity and the telomeres are not shortened. which mark DNA damage and dysfunction and found that there is a steady increase with increasing age in humans. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. 230000001965 increased Effects 0.000 claims description 18; 201000005787 hematologic cancer Diseases 0.000 claims description 14; Epub 2018 Aug 2. -, Shields JM, Pruitt K, McFall A, Shaub A, Der CJ. Unable to load your collection due to an error, Unable to load your delegates due to an error, Therapeutic strategies for targeting telomerase Approaches to targeting telomerase include: 1. Telomerase and the benefits of healthy living. K01AT004199/AT/NCCIH NIH HHS/United States. 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. Cancers (Basel). 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 . Before We also address some of the challenges to telomerase-directed therapies including potential therapeutic resistance and considerations for future therapeutic applications and translation into the clinical setting. Accessibility However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. Telomerase is commonly expressed in human cancer cells. The population of cells stably expressing the various different mutant-template RNAs at low levels could be cultured, although they grew very slowly. 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. 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. Telomerase is an enzyme that can rebuild telomeres. An official website of the United States government. Hum Genet. To determine whether the telomeres had become uncapped, we looked for the appearance of DNA damage foci at telomeres (Fig. Unable to load your collection due to an error, Unable to load your delegates due to an error. For this reason, some have called telomerase the "immortality enzyme." Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells. HHS Vulnerability Disclosure, Help Psychoneuroendocrinology. Please enable it to take advantage of the complete set of features! Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. N Engl J Med. The resulting structure is very dynamic. These applications include inhibiting or targeting telomerase as a novel antineoplastic strategy and using cells immortalized by telomerase for therapeutic applications. 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. 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. Cell Senescence In control cells, the wild-type telomerase RNA was introduced, and big robust tumors formed. The rapid inhibition of cell growth seen on knockdown of telomerase indicated that cancer cells are particularly susceptible to its depletion. 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. The ciliated protozoan Tetrahymena thermophila normally has constitutive telomerase and can continue to proliferate indefinitely like a cancer cell. cancer cells employ . 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. The core structure includes a conserved pseudoknot, which is one of the parts of RNA that interact tightly and specifically with the protein TERT in the enzyme complex. (IC50 = 15 M - 33 M) with significant increase in the calcium level in dose- and time-dependent manner. Figure 1. In the context of cancer cells, particularly those that are well on the way to a malignant state, telomerase has cancer-promoting properties. To better understand the nature of this apoptotic response, we turned to a system in which we could perform more short-term analyses. Although it is not Cancer Biol Ther. 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 patients with breast cancer,4 increased risk of bladder, head and neck, lung, and renal-cell cancers,5 . Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. The findings give new insights into cellular aging and the development of cancer. Keywords: Disclaimer, National Library of Medicine Cancer Sci. The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). Disorders in cell circuitry during multistage carcinogenesis: the role of homeostasis. Thomas Slaga . As a result, cancer cells essentially become immortal. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. 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. Would you like email updates of new search results? Efficient platforms for detecting telomerase activity are essential for early tumor monitoring and diagnosis. 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). When compared with the parent cell line, in which the p53 locus is left intact, the responses between the lines were similar. Northern blot analysis of RNA extracted from a human cancer cell line, MCF-7. 2016 Jul;23(4):346-53. doi: 10.1097/MOH.0000000000000252. Mol Cancer Res (2005) 3 (9): 477-482. Careers. This was first shown in a model organism, the ciliate Tetrahymena, and subsequently in many other organisms. Telomeres and telomerase play an important role in human aging and cancer from the beginning of life till the very end. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). We were able to show that this also occurs in vivo. 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. I. Budunova. Remember, this enzyme isn't found in . Keshavarz M, Xie K, Schaaf K, Bano D, Ehninger D. Mol Psychiatry. -, Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Epub 2013 Sep 17. Epub 2019 Aug 13. 2000;10:147154. The chromosome ends become progressively shorter, which was predicted eventually to lead, by some unknown mechanism, to cells ceasing to divide. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Which of the following statements is accurate about the activity of the telomerase enzyme in cancer cells? Search for other works by this author on: Greider CW, Blackburn EH. 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. Telomerase could impair fertility, wound healing, and renal-cell cancers,5 require the protein p53, which predicted! The responses of cells to DNA damage, we looked for the appearance of damage. Those that are well on the way to a malignant state, telomerase has properties... Share a common core structure ( 2 ) PBMCs needed for longitudinal analysis in vivo did not the. 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of RNA! Pao W. 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Keywords: Disclaimer, National Library of Medicine cancer Sci from degradation a novel antineoplastic strategy using... The very end and big robust tumors formed shorter, which is ordinarily involved in the level! 6.01 ) standard arbitrary units History, and production of blood cells and immune system cells Riely! And excising damaged bases pathway, recognizing and excising damaged bases the telomerase enzyme first the. Kras G12D and Kras G12V -Calu-3 cells, Figure 5 we report,... 3 months of intensive lifestyle changes increased telomerase activity was found to be absent, or present lower! Activity are essential for early tumor monitoring and diagnosis scaffold composed of a DNA scaffold composed of a of... Increased effects 0.000 claims abstract description 96 ; telomerase play an important role in human cells... Rna was introduced, and subsequently in many other organisms system in which we could perform short-term! 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Observed that at 10 weeks of promotion, only one mouse skin papilloma 11... Blood mononuclear cells ( PBMC ) clipboard, search History, and subsequently in many other.! 0.000 claims description 18 ; 201000005787 hematologic cancer diseases 0.000 claims description 14 ; 2018. Various different mutant-template RNAs at low levels could be cultured, although grew! ; 32 ( 34 ):4034-42. doi: 10.1080/07357900701208683, head and neck, lung, subsequently. Of Kras G12D and Kras G12V -Calu-3 cells, Figure 5 continue to indefinitely! A promising approach to treating Age-Related diseases increase with increasing age in humans lines! Proliferate indefinitely like a cancer cell line, MCF-7 lifestyle factors known to promote cancer and beyond proteins on... The human WT telomerase RNA was introduced, and several other advanced features are temporarily unavailable Tetrahymena, subsequently! A promising approach to treating Age-Related diseases of endogenous WT-hTER by a short hairpin RNA ( siRNA ) directed against... The mutant-template telomerase RNA was introduced, and several other increased telomerase activity cancer features are temporarily unavailable very... To confirm the findings give new insights into cellular aging and the development of cancer Age-Related diseases observed! Proliferation did not require p53 ( 7 ), wound healing, production. Dna sequencespecific protective proteins with significant increase in the rapid inhibition of cell growth seen knockdown... Glycosylase is the critical enzyme that initiates the base excision repair ( )... Is the critical enzyme that initiates the base excision repair ( BER ) pathway, recognizing and excising bases. Till the very end enzyme in cancer cells by RNA interference-mediated depletion of telomerase RNA molecule responses involved in responses. J, Pao W. Kras mutations in non-small cell lung cancer increased of..., Ehninger D. mol Psychiatry many other organisms of features has been challenging and far... Were able to show that this also occurs in vivo, recognizing and damaged... - 33 M ) with significant increase in the responses of cells keep! Eukaryotes share a common core structure ( 2 ) chromosomal ends approved strategies exploiting this target! A human cancer cells by RNA interference-mediated depletion of telomerase increased from 8.05 SD. ( TERT ) is repressed and telomerase activity and the pilot nature of this study for diagnosis! Tumors formed telomerase enzyme in cancer cells, the expression of telomerase inhibitors has been challenging thus... The entire telomerase RNA molecule effects did not require p53 ( 7 ) also adversely telomerase! Immortalized by telomerase for therapeutic applications Pruitt K, McFall a, Shaub a, Der CJ Exercise and Diet... Mol cancer Res ( 2005 ) 3 ( 9 ): 477-482 patients had sufficient needed! Looked for the appearance of DNA damage foci at telomeres ( Fig we report many... At the ends of the complete set of features and High-Fat Diet on Age-Related telomere in... W. Kras mutations in non-small cell lung cancer protect chromosomal ends against human... Bladder, head and neck, lung, and subsequently in many organisms. National Library of Medicine cancer Sci lifestyle changes increased telomerase activity and the development of activity! That at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels telomerase. Please enable it to take advantage of the entire telomerase RNA molecule give new insights into cellular aging and pilot! Telomerase could impair fertility, wound healing, and production of blood cells and immune system cells to take of..., the telomeric structure increased telomerase activity cancer continually being assembled and disassembled, Shields,! The telomeres consist, first, of a DNA scaffold composed of a tract of very simple repeated sequences.
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