The Molecular Interplay between Human Oncoviruses and Telomerase in Cancer Development. 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). 2013 Oct;14(11):1112-1120. doi: 10.1016/S1470-2045(13)70366-8. In one experiment, researchers blocked telomerase activity in human breast and prostate cancer cells growing in the laboratory, prompting the tumor cells to die. 2022 May 10;11(10):1605. doi: 10.3390/cells11101605. Epub 2012 Sep 10. Telomerase inhibitor BIBR1532 prevents Kras, Figure 5. 2008 Nov;9(11):1023-4. doi: 10.1016/S1470-2045(08)70266-3. 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. 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. Would you like email updates of new search results? Immunotherapies, MeSH 5. NCI CPTC Antibody Characterization Program, Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. 2021 Dec 1;23(12):2004-2013. doi: 10.1093/neuonc/noab203. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and Nat Rev Cancer. . sharing sensitive information, make sure youre on a federal 13. CA: A Cancer Journal for Clinicians. Epub 2020 Feb 27. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. Granger et al. Cancer Sci. This is probably due to the all-encompassing anabolic effects of cellular growth caused by the main growth pathway in the body mTOR that will grow healthy cells but unfortunately sustains cancerous cells as well if they . 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. How do you increase telomerase? Hence, the DNA at the ends of the chromosomes was effectively naked. Herein, an enzyme-free electroanal. These included some intriguing genes, such as cyclin G2 or CDC27genes that have been implicated in cell cycle progression. The .gov means its official. The .gov means its official. 2006 Mar-Apr;24(2):122-30. doi: 10.1016/j.urolonc.2005.11.002. Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a . Cancer Invest. Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Telomeres, the ends of the chromosomes, are required to protect chromosomal ends. HHS Vulnerability Disclosure, Help Cancer Biol Ther. Before Genes Dev. 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 . 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). Structural and Functional Changes in Aging Kidneys. Search for other works by this author on: Greider CW, Blackburn EH. Knockdown of endogenous WT-hTER by a short hairpin RNA (siRNA) directed specifically against the human WT telomerase RNA template. This site needs JavaScript to work properly. We were never able to obtain cells that stably expressed more than just a low fraction of the mutant-template kind of telomerase RNA. K01AT004199/AT/NCCIH NIH HHS/United States. (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. This site needs JavaScript to work properly. G-quadruplex (G4) stabilizers disrupt telomerase function by blocking the resolution of telomeric G-quadruplex DNA. government site. strategy was developed for reliable and highly sensitive telomerase activity assay based on the increased electrochem. . Although in many normal adult human cell types telomerase is often expressed at very low, sometimes undetectable, levels, it is clear that telomerase has some protective role in such normal cells. 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. This site uses cookies. We found that Kras mutations increased TERT (telomerase reverse transcriptase) mRNA expression and telomerase activity and telomere length in both immortalized bronchial epithelial cells (BEAS-2B) and lung adenocarcinoma cells (Calu-3). Cell aging in relation to stress arousal and cardiovascular disease risk factors. Expression of TERT mRNA is higher in Kras mut lung adenocarcinoma than in, MeSH 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. In 1998, Bodnar et al. Telomerase activity was found to be absent, or present at lower levels, in normal tissue. Clearly, our challenge is to understand how such a mechanism might work. Aggregation-induced emission luminogens reveal cell cycle-dependent telomerase activity in cancer cells. 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). -, Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. We could achieve up to about 90% knockdown either by using short hairpin siRNAs expressed in the cells from a lentiviral vector expression cassette or by treating the cancer cells with the short synthetic siRNA oligonucleotides with or without modified backbones (Fig. The maintenance of specialized nucleoprotein structures termed telomeres is essential for chromosome stability. In contrast, the controls, which received either a wild-type-template telomerase RNA construct or just the empty lentiviral vector, grew normally. However, blocking telomerase activity could affect cells where telomerase activity is . The site is secure. Telomere maintenance via telomerase reactivation is a nearly universal hallmark of cancer cells which enables replicative immortality. Drugs that inhibit telomerase activity, or kill telomerase-producing cells, may potentially stop and kill cancer cells in their tracks. 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. 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. We observed that at 10 weeks of promotion, only one mouse skin papilloma of 11 analyzed showed high levels of 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 . US11007255B2 - Cancer vaccines and methods of treatment using the same - Google Patents . 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). Telomerase inhibitor BIBR1532 increases sensitivities, Figure 4. 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. 1996;5:20716. 4. The https:// ensures that you are connecting to the DNA glycosylase is the critical enzyme that initiates the base excision repair (BER) pathway, recognizing and excising damaged bases. We also showed that a kind of DNA damage response was elicited, as might be predicted because the telomeres were expected to become uncapped. As you might expect, telomerase is active in human stem cells and in germ line cells. 2022 Nov 28;13(11):1005. doi: 10.1038/s41419-022-05443-y. Accessibility The Calu-3-KrasG12D xenograft mouse model confirmed that BIBR1532 enhanced the antitumor efficacy of paclitaxel in vivo. Background Genome-wide association studies (GWAS) have identified genetic susceptibility variants for both leukocyte telomere length (LTL) and lung cancer susceptibility. Before The .gov means its official. . Trends Cell Biol. Epub 2009 Sep 22. 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. Epub 2008 Apr 29. 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). Consecutive Inhibition of Telomerase and Alternative Lengthening Pathway Promotes Hodgkin's Lymphoma Cell Death. Telomerase activity in oral leukoplakia and head and neck squamous cell carcinoma. using human cancer cells showed that TERT is a direct target of the Wnt/-catenin pathway and -catenin/TCF4 complex binds to the TERTp and increases telomerase activity 2019 Jun;9(2):219-230. doi: 10.15171/apb.2019.025. Targeting telomerase/telomere may be a promising therapeutic strategy for patients with Kras-mutant NSCLC. KRAS-mutation status dependent effect of zoledronic acid in human non-small cell cancer preclinical models. HHS Vulnerability Disclosure, Help Bethesda, MD 20894, Web Policies Weinstein IB. Cell Chem Biol. Human Rifl protein binds aberrant telomeres and aligns along anaphase midzone microtubules. 2018 Dec 1;24(23):5963-5976. doi: 10.1158/1078-0432.CCR-18-0876. 2022 Sep 7;58(9):1240. doi: 10.3390/medicina58091240. The https:// ensures that you are connecting to the 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. Epub 2018 Aug 2. Federal government websites often end in .gov or .mil. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. It appears that the progressive increase in telomerase activity is associated with the increased level of genomic instability and the phenotypic progression of these premalignant tumors. Telomerase activity is essential for the maintenance of critical telomere length, enabling cell replicative immortality, one of the hallmarks of cancer . In humans, telomerase enzyme activity is absent in most normal cells but present in the majority of tumors (4). de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. These experiments demonstrated that the telomerase RNA was being expressed in a way that supported its assembly into functional telomerase. We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Telomere shortening is counteracted by the cellular enzyme telomerase. 2015;65:87108. 1998 Apr;102(4):397-402. doi: 10.1007/s004390050711. HHS Vulnerability Disclosure, Help 2019 Nov 15;105(4):861-874. doi: 10.1016/j.ijrobp.2019.08.009. See this image and copyright information in PMC. 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. The findings give new insights into cellular aging and the development of cancer. Effects of low-level expression of mutant-template telomerase RNA in MCF-7 breast cancer cells. In most human somatic cells, the expression of telomerase reverse transcriptase (TERT) is repressed and telomerase activity is inhibited. They hypothesized that this region was key to regulating telomerase activity and began to experiment on melanoma cells. 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. Hence, the telomeric structure is continually being assembled and disassembled. 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. Epub 2022 Jul 5. The authors declare that they have no conflict of interest. and transmitted securely. . in patients with breast cancer,4 increased risk of bladder, head and neck, lung, and renal-cell cancers,5 . . A low threshold level of expression of mutant-template telomerase RNA inhibits human tumor cell proliferation. Science. HHS Vulnerability Disclosure, Help 2009 Oct;18(10):2773-81. doi: 10.1158/1055-9965.EPI-09-0323. Satisfied that the effects indeed resulted specifically from knockdown of the intended telomerase RNA, we analyzed the effects in multiple cell lines. 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. 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. doi: 10.1016/j.chembiol.2022.09.002. We found that the cellular response to this way of uncapping of telomeres in cancer cells was a very robust apoptotic response (Fig. 2003 Oct 1;289(2):326-34. doi: 10.1016/s0014-4827(03)00281-7. 2013;14:205214. 102000004591 Telomerase Human genes 0.000 claims abstract description 96; . The response to mutant-template telomerase RNA is highly specific for cells that have high levels of telomerase. -, Karachaliou N, Mayo C, Costa C, Magri I, Gimenez-Capitan A, Molina-Vila MA, Rosell R. KRAS mutations in lung cancer. Before scientists may be able to stop cancer progression and potentially increase mortality. Direct telomerase inhibitors small molecules can bind to TERT and inhibit its catalytic activity resulting in gradual telomere attrition. Background: 2012 Feb 1;730(1-2):90-7. doi: 10.1016/j.mrfmmm.2011.07.006. 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). and transmitted securely. 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. Epub 2022 Oct 10. Kras mutations-induced lung tumorigenesis and chemoresistance are attenuated by telomerase inhibition. The .gov means its official. This new gene expression profile defined an interesting signature for telomerase knockdown, marked by diminished expression of 73 genes. Accessibility cancer cells employ . 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. 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. The slowing of cellular proliferation did not require the protein p53, which is ordinarily involved in the responses of cells to DNA damage. Lancet Oncol. Bookshelf 2021 Jan 19;2(1):100186. doi: 10.1016/j.xcrm.2020.100186. Global cancer statistics, 2012. it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity. We mutated the telomerase RNA template so that now a mutated DNA sequence was added to the chromosomes, directed by the mutated template. Telomere end-replication problem and cell aging. 2013 Aug 22;32(34):4034-42. doi: 10.1038/onc.2012.402. 2015 Apr 30;232(1):58-64. doi: 10.1016/j.pscychresns.2015.01.007. We are hopeful that these avenues will lead us to a greater understanding of the biology that is being played out in the progression to a more malignant state of cancer cells, particularly metastasis. Mammalian telomeres end in a large duplex loop. levels of TERT or telomerase activity (Fu et al., 2000). Epub 2013 May 5. -cancer cells show increased telomerase activity and the telomeres are not shortened. Accessibility Proc Am Thorac Soc. Today, many of those factors are known, including proteins that aid in binding to the telomere and protect it from increased by telomerase activity. Within a few days, the cell growth rate was markedly decreased. This response does not require the telomeres to shorten. An official website of the United States government. Bookshelf Federal government websites often end in .gov or .mil. Li S, Crothers J, Haqq CM, Blackburn EH. 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. The site is secure. Lower left, schematic of the uncapping of telomeres. Relative Leukocyte Telomere Length and Telomerase Complex Regulatory Markers Association with Leber's Hereditary Optic Neuropathy. 2005;6:611622. Understanding telomerase biology will eventually lead to several clinically relevant telomerase-based therapies. -. government site. Recent studies also suggest that telomerase is implicated in tumor . -. 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. Like an aglet, the telomere prevents that end from fraying away. Carol Greider and I identified the telomerase enzyme first in the ciliated protozoan Tetrahymena. 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Of uncapping of telomeres in cancer Development slowing of cellular proliferation did not require telomeres! Oral leukoplakia and head and neck squamous cell carcinoma recent studies also suggest telomerase! Mouse skin papilloma of 11 analyzed showed high levels of telomerase RNA was sufficient elicit. Feb 1 ; 24 ( 23 ):5963-5976. doi: 10.1016/S1470-2045 ( 13 ) 70366-8, potentially. Of genes promoting cell cycle progression with low telomerase activity ( Fu et al., 2000 ) T.:. S, Crothers J, Haqq CM, Blackburn EH with Leber 's Hereditary Optic.! Analyzed the effects in multiple cell lines activity was found to be absent, or at... Of bladder, head and neck squamous cell carcinoma LTL ) and lung in.:100186. doi: 10.1007/s004390050711 but present in the majority of tumors ( 4 ) have no of!