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Current Aging Science

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ISSN (Print): 1874-6098
ISSN (Online): 1874-6128

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Review Article

Telomerase Biology Associations Offer Keys to Cancer and Aging Therapeutics

Author(s): Joan Smith-Sonneborn*

Volume 13, Issue 1, 2020

Page: [11 - 21] Pages: 11

DOI: 10.2174/1874609812666190620124324

Abstract

Background: Although telomerase has potential for age-related disease intervention, the overexpression of telomerase in about 90% of cancers, and in HIV virus reservoirs, cautions against se in anti-aging telomerase therapeutics. While multiple reviews document the canonical function of telomerase for maintenance of telomeres, as well as an increasing numbers of reviews that reveal new non-canonical functions of telomerase, there was no systematic review that focuses on the array of associates of the subunit of Telomerase Reverse transcriptase protein (TERT) as pieces of the puzzle to assemble a picture of the how specific TERT complexes uniquely impact aging and age-related diseases and more can be expected.

Methods: A structured search of bibliographic data on TERT complexes was undertaken using databases from the National Center for Biotechnology Information Pubmed with extensive access to biomedical and genomic information in order to obtain a unique documented and cited overview of TERT complexes that may uniquely impact aging and age-related diseases.

Results: The TERT associations include proper folding, intracellular TERT transport, metabolism, mitochondrial ROS (Reactive Oxygen Species) regulation, inflammation, cell division, cell death, and gene expression, in addition to the well-known telomere maintenance. While increase of cell cycle inhibitors promote aging, in cancer, the cell cycle check-point regulators are ambushed in favor of cell proliferation, while cytoplasmic TERT protects a cell cycle inhibitor in oxidative stress. The oncogene cMyc regulates gene expression for overexpression of TERT, and reduction of cell cycle inhibitors-the perfect storm for cancer promotion. TERT binds with the oncogene RMRP RNA, and TERT-RMRP function can regulate levels of that oncogene RNA, and TERT in a TBN complex can regulate heterochromatin. Telomerase benefit and novel function in neurology and cardiology studies open new anti- aging hope. GV1001, a 16 amino acid peptide of TERT that associates with Heat Shock Proteins (HSP’s), bypasses the cell membrane with remarkable anti disease potential.

Conclusions: TERT “associates” are anti-cancer targets for downregulation, but upregulation in antiaging therapy. The overview revealed that unique TERT associations that impact all seven pillars of aging identified by the Trans-NIH Geroscience Initiative that influence aging and urge research for appropriate targeted telomerase supplements/ stimulation, and inclusion in National Institute on Aging Intervention Testing Program. The preference for use of available “smart drugs”, targeted to only cancer, not off-target anti- aging telomerase is implied by the multiplicity of TERT associates functions.

Keywords: Aging, TERT, associates, cancer, oncogenes, cell cycle, diseases, viral infection.

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Graphical Abstract

[1]
Huang DS, Wang Z, He XJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer 2015; 51(8): 969-76.
[http://dx.doi.org/10.1016/j.ejca.2015.03.010] [PMID: 25843513]
[2]
Chiba K, Lorbeer FK, Shain AH, et al. Mutations in the promoter of the telomerase gene TERT contribute to tumorigenesis by a two-step mechanism. Science 2017; 357(6358): 1416-20.
[http://dx.doi.org/10.1126/science.aao0535] [PMID: 28818973]
[3]
Heidenreich B, Kumar R. TERT promoter mutations in telomere biology. Mutat Res 2017; 771: 15-31.
[http://dx.doi.org/10.1016/j.mrrev.2016.11.002] [PMID: 28342451]
[4]
Lee DD, Leão R, Komosa M, et al. DNA hypermethylation within TERT promoter upregulates TERT expression in cancer. J Clin Invest 2019; 129(1): 223-9.
[http://dx.doi.org/10.1172/JCI121303] [PMID: 30358567]
[5]
Lewis KA, Tollefsbol TO. Regulation of the telomerase reverse transcriptase subunit through epigenetic mechanisms. Front Genet 2016; 7: 83.
[http://dx.doi.org/10.3389/fgene.2016.00083] [PMID: 27242892]
[6]
Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985; 43(2 Pt 1): 405-13.
[http://dx.doi.org/10.1016/0092-8674(85)90170-9] [PMID: 3907856]
[7]
Greider CW, Blackburn EH. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 1987; 51(6): 887-98.
[http://dx.doi.org/10.1016/0092-8674(87)90576-9] [PMID: 3319189]
[8]
Saretzki G. Telomeres, telomerase and ageing. Subcell Biochem 2018; 90: 221-308.
[http://dx.doi.org/10.1007/978-981-13-2835-0_9] [PMID: 30779012]
[9]
Amano H, Chaudhury A, Rodriguez-Aguayo C, et al. Telomere dysfunction induces sirtuin repression that drives telomere-dependent disease. Cell Metab 2019; S1550-413(19): 30129-9.
[10]
Haendeler J, Dröse S, Büchner N, et al. Mitochondrial telomerase reverse transcriptase binds to and protects mitochondrial DNA and function from damage. Arterioscler Thromb Vasc Biol 2009; 29(6): 929-35.
[http://dx.doi.org/10.1161/ATVBAHA.109.185546] [PMID: 19265030]
[11]
Haendeler J, Hoffmann J, Brandes RP, Zeiher AM, Dimmeler S. Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. Mol Cell Biol 2003; 23(13): 4598-610.
[http://dx.doi.org/10.1128/MCB.23.13.4598-4610.2003] [PMID: 12808100]
[12]
Saretzki G. Extra-telomeric functions of human telomerase: cancer, mitochondria and oxidative stress. Curr Pharm Des 2014; 20: 6386-403.
[http://dx.doi.org/10.2174/1381612820666140630095606]
[13]
Jaskelioff M, Muller FL, Paik JH, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011; 469(7328): 102-6.
[http://dx.doi.org/10.1038/nature09603] [PMID: 21113150]
[14]
Effros RB. Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp Gerontol 2011; 46(2-3): 135-40.
[http://dx.doi.org/10.1016/j.exger.2010.08.027] [PMID: 20833238]
[15]
Ait-Aissa K, Ebben JD, Kadlec AO, Beyer AM. Friend or foe? Telomerase as a pharmacological target in cancer and cardiovascular disease. Pharmacol Res 2016; 111: 422-33.
[http://dx.doi.org/10.1016/j.phrs.2016.07.003] [PMID: 27394166]
[16]
Quryshi N, Norwood TLE, Ait-Aissa K, Kong A, Beyer AM. Chemotherapeutic-induced cardiovascular dysfunction: Physiological effects, early detection-the role of telomerase to counteract mitochondrial defects and oxidative stress. Int J Mol Sci 2018; 10; 19(3): E797.
[17]
Zhou QG, Hu Y, Wu DL, et al. Hippocampal telomerase is involved in the modulation of depressive behaviors. J Neurosci 2011; 31(34): 12258-69.
[http://dx.doi.org/10.1523/JNEUROSCI.0805-11.2011] [PMID: 21865469]
[18]
Zhou QG, Liu MY, Lee HW, et al. Hippocampal TERT regulates spatial memory formation through modulation of neural development. Stem Cell Reports 2017; 9(2): 543-56.
[http://dx.doi.org/10.1016/j.stemcr.2017.06.014] [PMID: 28757168]
[19]
Avin BA, Umbricht CB, Zeiger MA. Human telomerase reverse transcriptase regulation by DNA methylation, transcription factor binding and alternative splicing (Review). Int J Oncol 2016; 49(6): 2199-205.
[http://dx.doi.org/10.3892/ijo.2016.3743] [PMID: 27779655]
[20]
Zhu J, Zhao Y, Wang S. Chromatin and epigenetic regulation of the telomerase reverse transcriptase gene. Protein Cell 2010; 1(1): 22-32.
[PMID: 21203995]
[21]
Liu X, Wang Y, Chang G, Wang F, Wang F, Geng X. Alternative splicing of hTERT pre-mRNA: A potential strategy for the regulation of telomerase activity. Int J Mol Sci 2017; 18(3): E567
[http://dx.doi.org/10.3390/ijms18030567] [PMID: 28272339]
[22]
Kalaydina RV, Bajwa K, Qorri B, Decarlo A, Szewczuk MR. Recent advances in “smart” delivery systems for extended drug release in cancer therapy. Int J Nanomedicine 2018; 13: 4727-45.
[http://dx.doi.org/10.2147/IJN.S168053] [PMID: 30154657]
[23]
Chan MS, Liu LS, Leung HM, Lo PK. Cancer-cell-specific mitochondria-targeted drug delivery by dual-ligand-functionalized nanodiamonds circumvent drug resistance. ACS Appl Mater Interfaces 2017; 9(13): 11780-9.
[http://dx.doi.org/10.1021/acsami.6b15954] [PMID: 28291330]
[24]
Lee SA, Kim BR, Kim BK, et al. Heat shock protein-mediated cell penetration and cytosolic delivery of macromolecules by a telomerase-derived peptide vaccine. Biomaterials 2013; 34(30): 7495-505.
[http://dx.doi.org/10.1016/j.biomaterials.2013.06.015] [PMID: 23827187]
[25]
Dai DF, Chiao YA, Marcinek DJ, Szeto HH, Rabinovitch PS. Mitochondrial oxidative stress in aging and healthspan. Longev Healthspan 2014; 3: 6.
[http://dx.doi.org/10.1186/2046-2395-3-6] [PMID: 24860647]
[26]
De Punder K, Heim C, Wadhwa PD, Entringer S. Stress and immunosenescence: The role of telomerase. Psychoneuroendocrinology 2019; 101: 87-100.
[http://dx.doi.org/10.1016/j.psyneuen.2018.10.019] [PMID: 30445409]
[27]
Soysal P, Isik AT, Carvalho AF, et al. Oxidative stress and frailty: A systematic review and synthesis of the best evidence. Maturitas 2017; 99: 66-72.
[http://dx.doi.org/10.1016/j.maturitas.2017.01.006] [PMID: 28364871]
[28]
Mikhed Y, Daiber A, Steven S. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. Int J Mol Sci 2015; 16(7): 15918-53.
[http://dx.doi.org/10.3390/ijms160715918] [PMID: 26184181]
[29]
Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem 2001; 276(19): 15571-4.
[http://dx.doi.org/10.1074/jbc.C100055200] [PMID: 11274138]
[30]
Freund A, Zhong FL, Venteicher AS, et al. Proteostatic control of telomerase function through TRiC-mediated folding of TCAB1. Cell 2014; 159(6): 1389-403.
[http://dx.doi.org/10.1016/j.cell.2014.10.059] [PMID: 25467444]
[31]
Chen L, Roake CM, Freund A, et al. An activity switch in human telomerase based on RNA conformation and shaped by TCAB1. Cell 2018; 174(1): 218-30.
[http://dx.doi.org/10.1016/j.cell.2018.04.039] [PMID: 29804836]
[32]
Jeong YY, Her J, Oh SY, Chung IK. Hsp90-binding immunophilin FKBP52 modulates telomerase activity by promoting the cytoplasmic retrotransport of hTERT. Biochem J 2016; 473(20): 3517-32.
[http://dx.doi.org/10.1042/BCJ20160344] [PMID: 27503910]
[33]
Lagadari M, Zgajnar NR, Gallo LI, Galigniana MD. Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity. Mol Oncol 2016; 10(7): 1086-98.
[http://dx.doi.org/10.1016/j.molonc.2016.05.002] [PMID: 27233944]
[34]
Pomplun S, Sippel C, Hähle A, et al. Chemogenomic profiling of human and microbial FK506-binding proteins. J Med Chem 2018; 61(8): 3660-73.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00137] [PMID: 29578710]
[35]
Hekmatimoghaddam S, Zare-Khormizi MR, Pourrajab F. Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases. Biofactors 2017; 43(6): 737-59.
[http://dx.doi.org/10.1002/biof.1264] [PMID: 26899445]
[36]
Ahmed S, Passos JF, Birket MJ, et al. Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. J Cell Sci 2008; 121(Pt 7): 1046-53.
[http://dx.doi.org/10.1242/jcs.019372] [PMID: 18334557]
[37]
Balasubramaniam M, Reis RJS, Phil D, et al. Involvement of tRNAs in replication of human mitochondrial DNA and modifying effects of telomerase. Mech Ageing Dev 2017; S0047-6374(17): 30095-7.
[http://dx.doi.org/10.1016/j.mad.2017.07.004]
[38]
Stojkovič G, Makarova AV, Wanrooij PH, Forslund J, Burgers PM, Wanrooij S. Oxidative DNA damage stalls the human mitochondrial replisome. Sci Rep 2016; 6: 28942.
[http://dx.doi.org/10.1038/srep28942] [PMID: 27364318]
[39]
Indran IR, Hande MP, Pervaiz S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res 2011; 71(1): 266-76.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-1588] [PMID: 21071633]
[40]
Green PD, Sharma NK, Santos JH. Telomerase impinges on the cellular response to oxidative stress through mitochondrial ros-mediated regulation of autophagy. Int J Mol Sci 2019; 20: E1509
[http://dx.doi.org/10.3390/ijms20061509] [PMID: 30917518]
[41]
Miwa S, Czapiewski R, Wan T, et al. Decreased mTOR signalling reduces mitochondrial ROS in brain via accumulation of the telomerase protein TERT within mitochondria. Aging (Albany NY) 2016; 8(10): 2551-67.
[http://dx.doi.org/10.18632/aging.101089] [PMID: 27777385]
[42]
Miwa S, Saretzki G. Telomerase and mTOR in the brain: the mitochondria connection. Neural Regen Res 2017; 12(3): 358-61.
[http://dx.doi.org/10.4103/1673-5374.202922] [PMID: 28469639]
[43]
Perluigi M, Di Domenico F, Butterfield DA. mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis 2015; 84: 39-49.
[http://dx.doi.org/10.1016/j.nbd.2015.03.014] [PMID: 25796566]
[44]
Tramutola A, Lanzillotta C, Barone E, et al. Intranasal rapamycin ameliorates Alzheimer-like cognitive decline in a mouse model of Down syndrome. Transl Neurodegener 2018; 7: 28.
[http://dx.doi.org/10.1186/s40035-018-0133-9] [PMID: 30410750]
[45]
Di Domenico F, Tramutola A, Foppoli C, Head E, Perluigi M, Butterfield DA. mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia. Free Radic Biol Med 2018; 114: 94-101.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.08.009] [PMID: 28807816]
[46]
Richardson A, Galvan V, Lin AL, Oddo S. How longevity research can lead to therapies for Alzheimer’s disease: The rapamycin story. Exp Gerontol 2015; 68: 51-8.
[http://dx.doi.org/10.1016/j.exger.2014.12.002] [PMID: 25481271]
[47]
Dogan F, Biray Avci C. Correlation between telomerase and mTOR pathway in cancer stem cells. Gene 2018; 641: 235-9.
[http://dx.doi.org/10.1016/j.gene.2017.09.072] [PMID: 29074462]
[48]
Sundin T, Hentosh P. InTERTesting association between telomerase, mTOR and phytochemicals. Expert Rev Mol Med 2012; 14: e8
[http://dx.doi.org/10.1017/erm.2012.1] [PMID: 22455872]
[49]
Ahmad F, Dixit D, Sharma V, et al. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma. Cell Death Dis 2016; 7: e2213
[http://dx.doi.org/10.1038/cddis.2016.117] [PMID: 27148686]
[50]
Walker A, Singh A, Tully E, et al. Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation. Free Radic Biol Med 2018; 120: 407-13.
[http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.009] [PMID: 29649567]
[51]
Singh A, Happel C, Manna SK, et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis. J Clin Invest 2013; 123(7): 2921-34.
[http://dx.doi.org/10.1172/JCI66353] [PMID: 23921124]
[52]
Hennig P, Garstkiewicz M, Grossi S, Di Filippo M, French LE, Beer HD. The Crosstalk between Nrf2 and Inflammasomes. Int J Mol Sci 2018; 19(2): E562
[http://dx.doi.org/10.3390/ijms19020562] [PMID: 29438305]
[53]
Hou Y, Wang Y, He Q, et al. Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury. Behav Brain Res 2018; 336: 32-9.
[http://dx.doi.org/10.1016/j.bbr.2017.06.027] [PMID: 28851669]
[54]
Doitsh G, Galloway NL, Geng X, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014; 505(7484): 509-14.
[http://dx.doi.org/10.1038/nature12940] [PMID: 24356306]
[55]
Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: A Blossoming of relevance to human pathobiology. Cell 2017; 168(1-2): 37-57.
[http://dx.doi.org/10.1016/j.cell.2016.12.012] [PMID: 28086098]
[56]
Ghosh A, Saginc G, Leow SC, et al. Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol 2012; 14(12): 1270-81.
[http://dx.doi.org/10.1038/ncb2621] [PMID: 23159929]
[57]
Chung SS, Aroh C, Vadgama JV. Constitutive activation of STAT3 signaling regulates hTERT and promotes stem cell-like traits in human breast cancer cells. PLoS One 2013; 8(12): e83971
[http://dx.doi.org/10.1371/journal.pone.0083971] [PMID: 24386318]
[58]
Gizard F, Heywood EB, Findeisen HM, et al. Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb Vasc Biol 2011; 31(2): 245-52.
[http://dx.doi.org/10.1161/ATVBAHA.110.219808] [PMID: 21106948]
[59]
Yu H, Pardoll D, Jove R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9(11): 798-809.
[http://dx.doi.org/10.1038/nrc2734] [PMID: 19851315]
[60]
Chung SS, Wu Y, Okobi Q, et al. Proinflammatory cytokines IL-6 and TNF-α increased telomerase activity through NF-κB/STAT1/STAT3 activation, and withaferin a inhibited the signaling in colorectal cancer cells. Mediators Inflamm 2017; 2017: 5958429
[http://dx.doi.org/10.1155/2017/5958429] [PMID: 28676732]
[61]
Zhang Y, Kong W, Jiang J. Prevention and treatment of cancer targeting chronic inflammation: research progress, potential agents, clinical studies and mechanisms. Sci China Life Sci 2017; 60(6): 601-16.
[http://dx.doi.org/10.1007/s11427-017-9047-4] [PMID: 28639101]
[62]
Bagheri S, Nosrati M, Li S, et al. Genes and pathways downstream of telomerase in melanoma metastasis. Proc Natl Acad Sci USA 2006; 103(30): 11306-11.
[http://dx.doi.org/10.1073/pnas.0510085103] [PMID: 16847266]
[63]
Robey RB, Hay N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 2006; 25(34): 4683-96.
[http://dx.doi.org/10.1038/sj.onc.1209595] [PMID: 16892082]
[64]
Patra KC, Wang Q, Bhaskar PT, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013; 24(2): 213-28.
[http://dx.doi.org/10.1016/j.ccr.2013.06.014] [PMID: 23911236]
[65]
Roh JI, Kim Y, Oh J, et al. Hexokinase 2 is a molecular bridge linking telomerase and autophagy. PLoS One 2018; 13(2): e0193182
[http://dx.doi.org/10.1371/journal.pone.0193182] [PMID: 29462198]
[66]
Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ 2015; 22(2): 364.
[http://dx.doi.org/10.1038/cdd.2014.208] [PMID: 25578149]
[67]
Roberts DJ, Tan-Sah VP, Ding EY, Smith JM, Miyamoto S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol Cell 2014; 53(4): 521-33.
[http://dx.doi.org/10.1016/j.molcel.2013.12.019] [PMID: 24462113]
[68]
Turner ML, Cronin JG, Noleto PG, Sheldon IM. Glucose availability and AMP-activated protein kinase link energy metabolism and innate immunity in the bovine endometrium. PLoS One 2016; 11(3): e0151416.
[http://dx.doi.org/10.1371/journal.pone.0151416] [PMID: 26974839]
[69]
Palmer CS, Hussain T, Duette G, et al. Regulators of glucose metabolism in CD4+ and CD8+ T cells. Int Rev Immunol 2016; 35(6): 477-88.
[http://dx.doi.org/10.3109/08830185.2015.1082178] [PMID: 26606199]
[70]
Rubtsova M, Naraykina Y, Vasilkova D, et al. Protein encoded in human telomerase RNA is involved in cell protective pathways. Nucleic Acids Res 2018; 46(17): 8966-77.
[http://dx.doi.org/10.1093/nar/gky705] [PMID: 30102362]
[71]
Ahmad F, Patrick S, Sheikh T, et al. Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma. J Neurochem 2017; 143(6): 671-83.
[http://dx.doi.org/10.1111/jnc.14152] [PMID: 28833137]
[72]
Maida Y, Yasukawa M, Furuuchi M, et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 2009; 461(7261): 230-5.
[http://dx.doi.org/10.1038/nature08283] [PMID: 19701182]
[73]
Maida Y, Yasukawa M, Masutomi K. De Novo RNA synthesis by RNA-dependent RNA polymerase activity 33 of telomerase reverse transcriptase. Mol Cell Biol 2016; 36(8): 1248-59.
[http://dx.doi.org/10.1128/MCB.01021-15] [PMID: 26830230]
[74]
Maida Y, Kyo S, Lassmann T, Hayashizaki Y, Masutomi K. Off-target effect of endogenous siRNA derived from RMRP in human cells. Int J Mol Sci 2013; 14(5): 9305-18.
[http://dx.doi.org/10.3390/ijms14059305] [PMID: 23629666]
[75]
Maida Y, Masutomi K. Telomerase reverse transcriptase moonlights: Therapeutic targets beyond telomerase. Cancer Sci 2015; 106(11): 1486-92.
[http://dx.doi.org/10.1111/cas.12806] [PMID: 26331588]
[76]
Mukherjee S, Firpo EJ, Wang Y, Roberts JM. Separation of telomerase functions by reverse genetics. Proc Natl Acad Sci USA 2011; 108(50): E1363-71.
[http://dx.doi.org/10.1073/pnas.1112414108] [PMID: 21949400]
[77]
Mattijssen S, Hinson ER, Onnekink C, et al. Viperin mRNA is a novel target for the human RNase MRP/RNase P endoribonuclease. Cell Mol Life Sci 2011; 68(14): 2469-80.
[http://dx.doi.org/10.1007/s00018-010-0568-3] [PMID: 21053045]
[78]
Goldfarb KC, Cech TR. Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing. Genes Dev 2017; 31(1): 59-71.
[http://dx.doi.org/10.1101/gad.286963.116] [PMID: 28115465]
[79]
Song H, Sun W, Ye G, et al. Long non-coding RNA expression profile in human gastric cancer and its clinical significances. J Transl Med 2013; 11: 225.
[http://dx.doi.org/10.1186/1479-5876-11-225] [PMID: 24063685]
[80]
Shao Y, Ye M, Li Q, Sun W, Ye G. LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer. Oncotarget 2016; 21: 37812- 824.
[http://dx.doi.org/10.18632/oncotarget.9336] [PMID: 27192121]
[81]
Meng Q, Ren M, Li Y, Song X. LncRNA-RMRP acts as an oncogene in lung cancer. PLoS One 2016; 11(12): e0164845
[http://dx.doi.org/10.1371/journal.pone.0164845] [PMID: 27906963]
[82]
Keklikoglou I, Hosaka K, Bender C, et al. MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 2015; 34(37): 4867-78.
[http://dx.doi.org/10.1038/onc.2014.408] [PMID: 25500542]
[83]
Pan J, Zhang D, Zhang J, Qin P, Wang J. LncRNA RMRP silence curbs neonatal neuroblastoma progression by regulating microRNA- 206/tachykinin-1 receptor axis via inactivating extracellular signal-regulated kinases. Cancer Biol Ther 2018; 24: 1-13.
[http://dx.doi.org/10.1080/15384047.2018.1550568] [PMID: 30582709]
[84]
De Paepe B, Lefever S, Mestdagh P. How long noncoding RNAs enforce their will on mitochondrial activity: regulation of mitochondrial respiration, reactive oxygen species production, apoptosis, and metabolic reprogramming in cancer. Curr Genet 2018; 64(1): 163-72.
[http://dx.doi.org/10.1007/s00294-017-0744-1] [PMID: 28879612]
[85]
Zhao Y, Sun L, Wang RR, Hu JF, Cui J. The effects of mitochondria-associated long noncoding RNAs in cancer mitochondria: New players in an old arena. Crit Rev Oncol Hematol 2018; 131: 76-82.
[http://dx.doi.org/10.1016/j.critrevonc.2018.08.005] [PMID: 30293709]
[86]
Wu S, Ge Y, Huang L, Liu H, Xue Y, Zhao Y. BRG1, the ATPase subunit of SWI/SNF chromatin remodeling complex, interacts with HDAC2 to modulate telomerase expression in human cancer cells. Cell Cycle 2014; 13(18): 2869-78.
[http://dx.doi.org/10.4161/15384101.2014.946834] [PMID: 25486475]
[87]
Wu Q, Lian JB, Stein JL, Stein GS, Nickerson JA, Imbalzano AN. The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics 2017; 9(6): 919-31.
[http://dx.doi.org/10.2217/epi-2017-0034] [PMID: 28521512]
[88]
Wang J, Wang L, Ji Q, Zhu H, Han S. Knockdown of Nucleostemin in an ovarian cancer SKOV-3 cell line and its effects on cell malignancy. Biochem Biophys Res Commun 2017; 487(2): 262-7.
[http://dx.doi.org/10.1016/j.bbrc.2017.04.046] [PMID: 28412352]
[89]
Okamoto N, Yasukawa M, Nguyen C, et al. Maintenance of tumor initiating cells of defined genetic composition by nucleostemin. Proc Natl Acad Sci USA 2011; 108(51): 20388-93.
[http://dx.doi.org/10.1073/pnas.1015171108] [PMID: 21730156]
[90]
Maida Y, Yasukawa M, Okamoto N, et al. Involvement of telomerase reverse transcriptase in heterochromatin maintenance. Mol Cell Biol 2014; 34(9): 1576-93.
[http://dx.doi.org/10.1128/MCB.00093-14] [PMID: 24550003]
[91]
Claycomb JM, Batista PJ, Pang KM, et al. The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation. Cell 2009; 139(1): 123-34.
[http://dx.doi.org/10.1016/j.cell.2009.09.014] [PMID: 19804758]
[92]
Sugiyama T, Cam H, Verdel A, Moazed D, Grewal SI. RNA-dependent RNA polymerase is an essential component of a self-enforcing loop coupling heterochromatin assembly to siRNA production. Proc Natl Acad Sci USA 2005; 102(1): 152-7.
[http://dx.doi.org/10.1073/pnas.0407641102] [PMID: 15615848]
[93]
Lassmann T, Maida Y, Tomaru Y, et al. Telomerase reverse transcriptase regulates microRNAs. Int J Mol Sci 2015; 16(1): 1192-208.
[http://dx.doi.org/10.3390/ijms16011192] [PMID: 25569094]
[94]
Masutomi K, Possemato R, Wong JM, et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc Natl Acad Sci USA 2005; 102(23): 8222-7.
[http://dx.doi.org/10.1073/pnas.0503095102] [PMID: 15928077]
[95]
Meena JK, Cerutti A, Beichler C, et al. Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion. EMBO J 2015; 34(10): 1371-84.
[http://dx.doi.org/10.15252/embj.201490070] [PMID: 25820263]
[96]
Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell 2006; 127(2): 265-75.
[http://dx.doi.org/10.1016/j.cell.2006.10.003] [PMID: 17055429]
[97]
He S, Sharpless NE. Senescence in health and disease. Cell 2017; 169(6): 1000-11.
[http://dx.doi.org/10.1016/j.cell.2017.05.015] [PMID: 28575665]
[98]
Wang Z, Gao J, Zhou J, Liu H, Xu C. Olaparib induced senescence under P16 or P53 dependent manner in ovarian cancer. J Gynecol Oncol 2019; 30(2): e26
[http://dx.doi.org/10.3802/jgo.2019.30.e26] [PMID: 30740957]
[99]
Liu JY, Souroullas GP, Diekman BO, et al. Cells exhibiting strong p16 INK4a promoter activation in vivo display features of senescence. Proc Natl Acad Sci USA 2019; 116(17): 2603-11.
[http://dx.doi.org/10.1073/pnas.1818313116] [PMID: 30683717]
[100]
Bazarov AV, Van Sluis M, Hines WC, et al. p16(INK4a) -mediated suppression of telomerase in normal and malignant human breast cells. Aging Cell 2010; 9(5): 736-46.
[http://dx.doi.org/10.1111/j.1474-9726.2010.00599.x] [PMID: 20569236]
[101]
Haga K, Ohno S, Yugawa T, et al. Efficient immortalization of primary human cells by p16INK4a-specific short hairpin RNA or Bmi-1, combined with introduction of hTERT. Cancer Sci 2007; 98(2): 147-54.
[http://dx.doi.org/10.1111/j.1349-7006.2006.00373.x] [PMID: 17233832]
[102]
Meng J, Tong Q, Liu X, Yu Z, Zhang J, Gao B. Epigallocatechin-3-gallate inhibits growth and induces apoptosis in esophageal cancer cells through the demethylation and reactivation of the p16 gene. Oncol Lett 2017; 14(1): 1152-6.
[http://dx.doi.org/10.3892/ol.2017.6248] [PMID: 28693288]
[103]
Moradzadeh M, Hosseini A, Erfanian S, Rezaei H. Epigallocatechin-3-gallate promotes apoptosis in human breast cancer T47D cells through down-regulation of PI3K/AKT and Telomerase. Pharmacol Rep 2017; 69(5): 924-8.
[http://dx.doi.org/10.1016/j.pharep.2017.04.008] [PMID: 28646740]
[104]
Hannon GJ, Beach D. p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 1994; 371(6494): 257-61.
[http://dx.doi.org/10.1038/371257a0] [PMID: 8078588]
[105]
Kumar R, Gont A, Perkins TJ, Hanson JEL, Lorimer IAJ. Induction of senescence in primary glioblastoma cells by serum and TGFβ. Sci Rep 2017; 7(1): 2156.
[http://dx.doi.org/10.1038/s41598-017-02380-1] [PMID: 28526854]
[106]
Del Bufalo D, Rizzo A, Trisciuoglio D, et al. Involvement of hTERT in apoptosis induced by interference with Bcl-2 expression and function. Cell Death Differ 2005; 12(11): 1429-38.
[http://dx.doi.org/10.1038/sj.cdd.4401670] [PMID: 15920535]
[107]
Cummins NW, Sainski-Nguyen AM, Natesampillai S, Aboulnasr F, Kaufmann S, Badley AD. Maintenance of the HIV reservoir is antagonized by selective BCL2 inhibition. J Virol 2017; 91(11): e00012-7.
[http://dx.doi.org/10.1128/JVI.00012-17] [PMID: 28331083]
[108]
Oh YS, Jeong SG, Cho GW. Anti-senescence effects of DNA methyltransferase inhibitor RG108 in human bone marrow mesenchymal stromal cells. Biotechnol Appl Biochem 2015; 62(5): 583-90.
[http://dx.doi.org/10.1002/bab.1393] [PMID: 25952632]
[109]
Brueckner B, Garcia BR, Siedlecki P, et al. Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res 2005; 65(14): 6305-11.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-2957] [PMID: 16024632]
[110]
Iannilli F, Zalfa F, Gartner A, Bagni C, Dotti CG. Cytoplasmic TERT associates to RNA granules in fully mature neurons: Role in the translational control of the cell cycle inhibitor p15INK4B. PLoS One 2013; 8(6): e66602
[http://dx.doi.org/10.1371/journal.pone.0066602] [PMID: 23825548]
[111]
Spilsbury A, Miwa S, Attems J, Saretzki G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J Neurosci 2015; 35(4): 1659-74.
[http://dx.doi.org/10.1523/JNEUROSCI.2925-14.2015] [PMID: 25632141]
[112]
Eitan E, Tichon A, Daniel G, Priel E. Telomerase expression in adult and old mouse Purkinje neurons. Rejuvenation Res 2012; 15(2): 206-9.
[http://dx.doi.org/10.1089/rej.2011.1285] [PMID: 22533433]
[113]
Eitan E, Braverman C, Tichon A, et al. Excitotoxic and radiation stress increase TERT levels in the mitochondria and cytosol of cerebellar purkinje neurons. Cerebellum 2016; 15(4): 509-17.
[http://dx.doi.org/10.1007/s12311-015-0720-6] [PMID: 26374457]
[114]
Koh CM, Khattar E, Leow SC, et al. Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity. J Clin Invest 2015; 125(5): 2109-22.
[http://dx.doi.org/10.1172/JCI79134] [PMID: 25893605]
[115]
Wu KJ, Grandori C, Amacker M, et al. Direct activation of TERT transcription by c-MYC. Nat Genet 1999; 21(2): 220-4.
[http://dx.doi.org/10.1038/6010] [PMID: 9988278]
[116]
Bouchard C, Thieke K, Maier A, et al. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J 1999; 18(19): 5321-33.
[http://dx.doi.org/10.1093/emboj/18.19.5321] [PMID: 10508165]
[117]
Staller P, Peukert K, Kiermaier A, et al. Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol 2001; 3(4): 392-9.
[http://dx.doi.org/10.1038/35070076] [PMID: 11283613]
[118]
Claassen GF, Hann SR. A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor β -induced cell-cycle arrest. Proc Natl Acad Sci USA 2000; 97(17): 9498-503.
[http://dx.doi.org/10.1073/pnas.150006697] [PMID: 10920185]
[119]
Zheng L, Suzuki H, Nakajo Y, Nakano A, Kato M. Regulation of c-MYC transcriptional activity by transforming growth factor-beta 1-stimulated clone 22. Cancer Sci 2018; 109(2): 395-402.
[http://dx.doi.org/10.1111/cas.13466] [PMID: 29224245]
[120]
Baena-Del V JA, Zheng Q, Esopi DM, et al. MYC drives overexpression of telomerase RNA (hTR/TERC) in prostate cancer. J Pathol 2018; 244(1): 11-24.
[http://dx.doi.org/10.1002/path.4980] [PMID: 28888037]
[121]
Eriksson PS, Perfilieva E, Björk-Eriksson T, et al. Neurogenesis in the adult human hippocampus. Nat Med 1998; 4(11): 1313-7.
[http://dx.doi.org/10.1038/3305] [PMID: 9809557]
[122]
Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, Frisén J. Retrospective birth dating of cells in humans. Cell 2005; 122(1): 133-43.
[http://dx.doi.org/10.1016/j.cell.2005.04.028] [PMID: 16009139]
[123]
Spalding KL, Bergmann O, Alkass K, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell 2013; 153(6): 1219-27.
[http://dx.doi.org/10.1016/j.cell.2013.05.002] [PMID: 23746839]
[124]
Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E. Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis. EMBO Mol Med 2012; 4(4): 313-29.
[http://dx.doi.org/10.1002/emmm.201200212] [PMID: 22351600]
[125]
Lieberwirth C, Pan Y, Liu Y, Zhang Z, Wang Z. Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory. Brain Res 2016; 1644: 127-40.
[http://dx.doi.org/10.1016/j.brainres.2016.05.015] [PMID: 27174001]
[126]
Fu W, Killen M, Culmsee C, Dhar S, Pandita TK, Mattson MP. The catalytic subunit of telomerase is expressed in developing brain neurons and serves a cell survival-promoting function. J Mol Neurosci 2000; 14: 3-15.
[127]
Khacho M, Slack RS. Mitochondrial dynamics in the regulation of neurogenesis: From development to the adult brain. Dev Dyn 2018; 247(1): 47-53.
[http://dx.doi.org/10.1002/dvdy.24538] [PMID: 28643345]
[128]
Liu MY, Nemes A, Zhou QG. The emerging roles for telomerase in the central nervous system. Front Mol Neurosci 2018; 11: 160.
[http://dx.doi.org/10.3389/fnmol.2018.00160] [PMID: 29867352]
[129]
Beyer AM, Freed JK, Durand MJ, et al. Critical role for telomerase in the mechanism of flow-mediated dilation in the human microcirculation. Circ Res 2016; 118(5): 856-66.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.307918] [PMID: 26699654]
[130]
Ait-Aissa K, Heisner JS, Norwood T LE, et al. Telomerase deficiency predisposes to heart failure and ischemia-reperfusion injury. Front Cardiovasc Med 2019; 6: 31.
[http://dx.doi.org/10.3389/fcvm.2019.00031] [PMID: 31001540]
[131]
Mouraret N, Houssaïni A, Abid S, et al. Role for telomerase in pulmonary hypertension. Circulation 2015; 131(8): 742-55.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.013258] [PMID: 25550449]
[132]
Sharifi-Sanjani M, Oyster NM, Tichy ED, et al. Cardiomyocyte-specific telomere shortening is a distinct signature of heart failure in humans. J Am Heart Assoc 2017; 7: 6.
[133]
Kim H, Seo EH, Lee SH, Kim BJ. The telomerase-derived anticancer peptide vaccine GV1001 as an extracellular heat shock protein-mediated cell-penetrating peptide. Int J Mol Sci 2016; 17(12): 2054.
[http://dx.doi.org/10.3390/ijms17122054]
[134]
Choi J, Kim H, Kim Y, et al. The anti-inflammatory effect of GV1001 mediated by the down regulation of ENO1-induced pro-inflammatory cytokine production. Immune Netw 2015; 15(6): 291-303.
[http://dx.doi.org/10.4110/in.2015.15.6.291] [PMID: 26770183]
[135]
Ko YJ, Kwon KY, Kum KY, et al. The anti-inflammatory effect of human telomerase-derived peptide on P. gingivalis lipopolysaccharide-induced inflammatory cytokine production and its mechanism in human dental pulp cells. Mediators Inflamm 2015; 2015: 385127
[http://dx.doi.org/10.1155/2015/385127] [PMID: 26604431]
[136]
Koo TY, Yan JJ, Yang J. Protective effect of peptide GV1001 against renal ischemia-reperfusion injury in mice. Transplant Proc 2014; 46(4): 1117-22.
[http://dx.doi.org/10.1016/j.transproceed.2013.12.019] [PMID: 24815142]
[137]
Lee SA, Kim J, Sim J, et al. A telomerase-derived peptide regulates reactive oxygen species and hepatitis C virus RNA replication in HCV-infected cells via heat shock protein 90. Biochem Biophys Res Commun 2016; 471(1): 156-62.
[http://dx.doi.org/10.1016/j.bbrc.2016.01.160] [PMID: 26828270]
[138]
Kim H, Choi MS, Inn KS, Kim BJ. Inhibition of HIV-1 reactivation by a telomerase-derived peptide in a HSP90-dependent manner. Sci Rep 2016; 6: 28896-906.
[http://dx.doi.org/10.1038/srep28896] [PMID: 27363520]
[139]
Park HH, Lee KY, Kim S, et al. Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase. Neurobiol Aging 2014; 35(6): 1255-74.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.015] [PMID: 24439482]
[140]
Chen W, Shin KH, Kim S, et al. hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling. Int J Mol Med 2018; 41(6): 3211-20.
[http://dx.doi.org/10.3892/ijmm.2018.3566] [PMID: 29568955]
[141]
Jakob S, Haendeler J. Molecular mechanisms involved in endothelial cell aging: role of telomerase reverse transcriptase. Z Gerontol Geriatr 2007; 40(5): 334-8.
[http://dx.doi.org/10.1007/s00391-007-0482-y] [PMID: 17943236]
[142]
Bernardes de Jesus B, Schneeberger K, Vera E, Tejera A, Harley CB, Blasco MA. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 2011; 10(4): 604-21.
[http://dx.doi.org/10.1111/j.1474-9726.2011.00700.x] [PMID: 21426483]
[143]
Zhang Y, Wang C, Jin Y, et al. Activating the PGC-1α/TERT pathway by catalpol ameliorates atherosclerosis via modulating ROS production, DNA damage, and telomere function: Implications on mitochondria and telomere link. Oxid Med Cell Longev 2018; 2018: 2876350
[http://dx.doi.org/10.1155/2018/2876350] [PMID: 30046372]
[144]
Smith SJ. How telomerase biology affects cancer biology, chemotherapy aging. Proceedings of the 36th World Cancer Conference. Oct 11-13 2018; Zurich Switzerland.
[http://dx.doi.org/10.21767/2254-6081-C4-013]

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