Telomerase reverse transcriptase: Difference between revisions

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{{for|the chemical descripter|Descriptor_(Chemistry)#sec-,_tert-}}
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{{Infobox_gene}}
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'''Telomerase reverse transcriptase''' (abbreviated to '''TERT''', or '''hTERT''' in humans) is a catalytic subunit of the [[enzyme]] [[telomerase]], which, together with the [[telomerase RNA component]] (TERC), comprises the  most important unit of the telomerase complex.<ref name=Weinrich>{{cite journal |vauthors=Weinrich SL, Pruzan R, Ma L, Ouellette M, Tesmer VM, Holt SE, Bodnar AG, Lichtsteiner S, Kim NW, Trager JB, Taylor RD, Carlos R, Andrews WH, Wright WE, Shay JW, Harley CB, Morin GB | title = Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT | journal = Nat. Genet. | volume = 17 | issue = 4 | pages = 498–502 |date=December 1997 | pmid = 9398860 | doi = 10.1038/ng1297-498 }}</ref><ref name="pmid11735173">{{cite journal |vauthors=Kirkpatrick KL, Mokbel K | title = The significance of human telomerase reverse transcriptase (hTERT) in cancer | journal = Eur J Surg Oncol | volume = 27 | issue = 8 | pages = 754–60 | year = 2001 | pmid = 11735173 | doi = 10.1053/ejso.2001.1151 }}</ref>
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Telomerases are part of a distinct subgroup of RNA-dependent polymerases.  Telomerase lengthens telomeres in [[DNA]] strands, thereby allowing senescent [[cell (biology)|cell]]s that would otherwise become postmitotic and undergo [[apoptosis]] to exceed the [[Hayflick limit]] and become potentially immortal, as is often the case with cancerous cells. To be specific, TERT is responsible for catalyzing the addition of [[nucleotides]] in a TTAGGG sequence to the ends of a [[chromosome]]’s [[telomere]]s.<ref name="pmid3277178">{{cite journal |vauthors=Shampay J, Blackburn EH | title = Generation of telomere-length heterogeneity in Saccharomyces cerevisiae | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 2 | pages = 534–8 |date=January 1988 | pmid = 3277178 | pmc = 279585 | doi = 10.1073/pnas.85.2.534}}</ref> This addition of repetitive [[DNA]] sequences prevents degradation of the chromosomal ends following multiple rounds of replication.<ref name="pmid11376932">{{cite journal |vauthors=Poole JC, Andrews LG, Tollefsbol TO | title = Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT) | journal = Gene | volume = 269 | issue = 1-2 | pages = 1–12 |date=May 2001 | pmid = 11376932 | doi = 10.1016/S0378-1119(01)00440-1 }}</ref>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Telomerase reverse transcriptase
| HGNCid = 11730
| Symbol = TERT
| AltSymbols =; EST2; TCS1; TP2; TRT; hEST2
| OMIM = 187270
| ECnumber = 
| Homologene = 31141
| MGIid = 1202709
| GeneAtlas_image1 = PBB_GE_TERT_207199_at_tn.png
<!-- The Following entry is a time stamp of the last bot update. It is typically hidden data -->
| DateOfBotUpdate = 07:45, 9 October 2007 (UTC)
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003721 |text = telomeric template RNA reverse transcriptase activity}} {{GNF_GO|id=GO:0003723 |text = RNA binding}} {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0016740 |text = transferase activity}} {{GNF_GO|id=GO:0042162 |text = telomeric DNA binding}}
| Component = {{GNF_GO|id=GO:0000781 |text = chromosome, telomeric region}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005694 |text = chromosome}} {{GNF_GO|id=GO:0005697 |text = telomerase holoenzyme complex}}
| Process = {{GNF_GO|id=GO:0000723 |text = telomere maintenance}} {{GNF_GO|id=GO:0006278 |text = RNA-dependent DNA replication}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7015
    | Hs_Ensembl = ENSG00000164362
    | Hs_RefseqProtein = NP_937983
    | Hs_RefseqmRNA = NM_198253
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 1306282
    | Hs_GenLoc_end = 1348162
    | Hs_Uniprot = O14746
    | Mm_EntrezGene = 21752
    | Mm_Ensembl = ENSMUSG00000021611
    | Mm_RefseqmRNA = NM_009354
    | Mm_RefseqProtein = NP_033380
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 74092992
    | Mm_GenLoc_end = 74115843
    | Mm_Uniprot = A0JNY9
  }}
}}
'''Telomerase reverse transcriptase''' is an [[enzyme]] associated with [[Cri du chat]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
hTERT absence (usually as a result of a [[chromosome|chromosomal]] [[mutation]]) is associated with the disorder [[Cri du chat]].<ref name="pmid12629597">{{cite journal |vauthors=Zhang A, Zheng C, Hou M, Lindvall C, Li KJ, Erlandsson F, Björkholm M, Gruber A, Blennow E, Xu D | title = Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome | journal = Am. J. Hum. Genet. | volume = 72 | issue = 4 | pages = 940–8 | year = 2003 | pmid = 12629597 | doi = 10.1086/374565| pmc = 1180356 }}</ref><ref name="pmid16953888">{{cite journal | author = Cerruti Mainardi P | title = Cri du Chat syndrome | journal = Orphanet J Rare Dis | volume = 1 | issue = | pages = 33 | year = 2006 | pmid = 16953888 | doi = 10.1186/1750-1172-1-33 | pmc = 1574300 }}</ref>
{{PBB_Summary
| section_title =  
| summary_text = Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component which serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mouse suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity.<ref>{{cite web | title = Entrez Gene: TERT telomerase reverse transcriptase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7015| accessdate = }}</ref>
}}


==References==
== Function ==
{{reflist|2}}
 
==Further reading==
[[Telomerase]] is a [[ribonucleoprotein]] [[polymerase]] that maintains [[telomere]] ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with [[reverse transcriptase]] activity, encoded by this gene, and an [[RNA]] component that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal [[somatic cell]]s, resulting in progressive shortening of telomeres. Studies in mice suggest that telomerase also participates in chromosomal repair, since [[de novo synthesis]] of [[telomere]] repeats may occur at [[DNA repair#Double-strand breaks|double-stranded break]]s. [[Alternative splicing|Alternatively spliced]] variants encoding different [[isoform]]s of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity.<ref name = "entrez">{{cite web | title = Entrez Gene: TERT telomerase reverse transcriptase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7015| accessdate = }}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
==Regulation of hTERT==
| citations =  
 
*{{cite journal | author=Mattson MP, Fu W, Zhang P |title=Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective. |journal=Mech. Ageing Dev. |volume=122 |issue= 7 |pages= 659-71 |year= 2001 |pmid= 11322991 |doi=  }}
The hTERT gene, located on chromosome 5, consists of 16 [[exons]] and 15 [[introns]] spanning 35 kb. The core promoter of hTERT includes 330 base pairs upstream of the translation start site (AUG since it's RNA by using the words "exons" and "introns"), as well as 37 base pairs of exon 2 of the hTERT gene.<ref name="Cong">{{cite journal |vauthors=Cong YS, Wen J, Bacchetti S | title = The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter | journal = Hum. Mol. Genet. | volume = 8 | issue = 1 | pages = 137–42 |date=January 1999 | pmid = 9887342 | doi = 10.1093/hmg/8.1.137 }}</ref><ref name="Bryce">{{cite journal |vauthors=Bryce LA, Morrison N, Hoare SF, Muir S, Keith WN | title = Mapping of the gene for the human telomerase reverse transcriptase, hTERT, to chromosome 5p15.33 by fluorescence in situ hybridization | journal = Neoplasia | volume = 2 | issue = 3 | pages = 197–201 | year = 2000 | pmid = 10935505 | pmc = 1507564 | doi =  10.1038/sj.neo.7900092}}</ref><ref name="Ćukušić">{{cite journal |vauthors=Ćukušić A, Skrobot Vidaček N, Sopta M, Rubelj I | title = Telomerase regulation at the crossroads of cell fate | journal = Cytogenet. Genome Res. | volume = 122 | issue = 3-4 | pages = 263–72 | year = 2008 | pmid = 19188695 | doi = 10.1159/000167812 | url = }}</ref> The hTERT promoter is GC-rich and lacks [[TATA box|TATA]] and [[CAAT box]]es but contains many sites for several [[transcription factors]] giving indication of a high level of regulation by multiple factors in many cellular contexts.<ref name=Cong/>  Transcription factors that can activate hTERT include many [[oncogenes]] (cancer-causing genes) such as [[c-Myc]], [[Sp1 transcription factor|Sp1]], [[Hypoxia-inducible factors|HIF-1]], [[Activating protein 2|AP2]], and many more, while many cancer suppressing genes such as [[p53]], [[WT1]], and [[MEN1|Menin]] produce factors that suppress hTERT activity .<ref name="Ćukušić"/><ref name="Kyo">{{cite journal |vauthors=Kyo S, Takakura M, Fujiwara T, Inoue M | title = Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers | journal = Cancer Sci. | volume = 99 | issue = 8 | pages = 1528–38 |date=August 2008 | pmid = 18754863 | doi = 10.1111/j.1349-7006.2008.00878.x }}</ref> Another form of [[up-regulation]] is through demethylation of [[histones]] proximal to the [[Promoter (genetics)|promoter]] region, imitating the low density of trimethylated histones seen in [[embryonic stem cells]].<ref name=Marion />  This allows for the recruitment of [[histone acetyltransferase]] (HAT) to unwind the sequence allowing for transcription of the gene.<ref name=Kyo/>
*{{cite journal  | author=Castillo Ureta H, Barrera Saldaña HA, Martínez Rodríguez HG |title=[Telomerase: an enzyme with multiple applications in cancer research] |journal=Rev. Invest. Clin. |volume=54 |issue= 4 |pages= 342-8 |year= 2003 |pmid= 12415959 |doi= }}
 
*{{cite journal  | author=Janknecht R |title=On the road to immortality: hTERT upregulation in cancer cells. |journal=FEBS Lett. |volume=564 |issue= 1-2 |pages= 9-13 |year= 2004 |pmid= 15094035 |doi= 10.1016/S0014-5793(04)00356-4 }}
Telomere deficiency is often linked to aging, cancers and the conditions [[dyskeratosis congenita]] (DKC) and [[Cri du chat]]. Meanwhile, [[Gene expression|over-expression]] of hTERT is often associated with cancers and tumor formation.<ref name="pmid12629597"/><ref name=Walne/><ref name="Flores">{{cite journal |vauthors=Flores I, Benetti R, Blasco MA | title = Telomerase regulation and stem cell behaviour | journal = Current Opinion in Cell Biology | volume = 18 | issue = 3 | pages = 254–60 |date=June 2006 | pmid = 16617011 | doi = 10.1016/j.ceb.2006.03.003 }}</ref><ref name="pmid22500192">{{cite journal |vauthors=Calado R, Young N | title = Telomeres in disease | journal = F1000 Med Rep | volume = 4 | issue = | pages = 8 | year = 2012 | pmid = 22500192 | pmc = 3318193 | doi = 10.3410/M4-8 }}</ref> The regulation of hTERT is extremely important to the maintenance of [[Stem cell|stem]] and cancer cells and can be used in multiple ways in the field of [[regenerative medicine]].
*{{cite journal  | author=Cristofari G, Sikora K, Lingner J |title=Telomerase unplugged. |journal=ACS Chem. Biol. |volume=2 |issue= 3 |pages= 155-8 |year= 2007 |pmid= 17373762 |doi= 10.1021/cb700037c }}
 
*{{cite journal | author=Beliveau A, Yaswen P |title=Soothing the watchman: telomerase reduces the p53-dependent cellular stress response. |journal=Cell Cycle |volume=6 |issue= 11 |pages= 1284-7 |year= 2007 |pmid= 17534147 |doi=  }}
== Stem cells ==
*{{cite journal | author=Bellon M, Nicot C |title=Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia. |journal=Cancer genomics & proteomics |volume=4 |issue= 1 |pages= 21-5 |year= 2007 |pmid= 17726237 |doi= }}
 
}}
=== hTERT in stem cells ===
{{refend}}
 
hTERT is often [[Up-regulation|up-regulated]] in cells that divide rapidly, including both [[embryonic stem cell]]s and [[adult stem cells]].<ref name=Flores /> It elongates the telomeres of [[stem cell]]s, which, as a consequence, increases the lifespan of the stem cells by allowing for indefinite division without shortening of telomeres. Therefore, it is responsible for the self-renewal properties of stem cells. Telomerase are found specifically to target shorter telomere over longer telomere, due to various regulatory mechanisms inside the cells that reduce the [[Chemical affinity|affinity]] of telomerase to longer telomeres. This preferential affinity maintains a balance within the cell such that the telomeres are of sufficient length for their function and yet, at the same time, not contribute to aberrant telomere elongation <ref name=Flores2>{{cite journal |vauthors=Flores I, Blasco MA | title = The role of telomeres and telomerase in stem cell aging | journal = FEBS Lett. | volume = 584 | issue = 17 | pages = 3826–30 |date=September 2010 | pmid = 20674573 | doi = 10.1016/j.febslet.2010.07.042 }}</ref>
High expression of hTERT is also often used as a landmark for [[pluripotency]] and [[multipotency]] state of embryonic and adult stem cells.  Over-expression of hTERT was found to [[Immortalization|immortalize]] certain cell types as well as impart different interesting properties to different stem cells.<ref name="Ćukušić"/><ref name="Tsai"/>
 
=== Immortalization ===
 
hTERT immortalizes various normal cells in culture, thereby endowing the self-renewal properties of stem cells to non-stem cell cultures.<ref name="Ćukušić"/><ref name="Kogan">{{cite journal |vauthors=Kogan I, Goldfinger N, Milyavsky M, Cohen M, Shats I, Dobler G, Klocker H, Wasylyk B, Voller M, Aalders T, Schalken JA, Oren M, Rotter V | title = hTERT-immortalized prostate epithelial and stromal-derived cells: an authentic in vitro model for differentiation and carcinogenesis | journal = Cancer Res. | volume = 66 | issue = 7 | pages = 3531–40 |date=April 2006 | pmid = 16585177 | doi = 10.1158/0008-5472.CAN-05-2183 }}</ref> There are multiple ways in which immortalization of non-stem cells can be achieved, one of which being via the introduction of hTERT into the cells.  Differentiated cells often express [[Telomerase RNA component|hTERC]] and TP1, a telomerase-associated protein that helps form the telomerase assembly, but does not express hTERT.  Hence, hTERT acts as the limiting factor for telomerase activity in differentiated cells <ref name="Ćukušić"/><ref name="pmid9425903">{{cite journal |vauthors=Nakayama J, Tahara H, Tahara E, Saito M, Ito K, Nakamura H, Nakanishi T, Tahara E, Ide T, Ishikawa F | title = Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas | journal = Nat. Genet. | volume = 18 | issue = 1 | pages = 65–8 |date=January 1998 | pmid = 9425903 | doi = 10.1038/ng0198-65 }}</ref> However, with hTERT over-expression, active telomerase can be formed in differentiated cells. This method has been used to immortalize prostate epithelial and stromal-derived cells, which are typically difficult to culture ''[[in vitro]]''. hTERT introduction allows ''in vitro'' culture of these cells and available for possible future research. hTERT introduction have an advantage over the use of viral protein for immortalization in that it does not involve the inactivation of [[tumor suppressor gene]], which might lead to cancer formation.<ref name="Kogan"/>
 
=== Enhancement of stem cell properties ===
 
Over-expression of hTERT in stem cells changes the properties of the cells.<ref name="Tsai">{{cite journal |vauthors=Tsai CC, Chen CL, Liu HC, Lee YT, Wang HW, Hou LT, Hung SC | title = Overexpression of hTERT increases stem-like properties and decreases spontaneous differentiation in human mesenchymal stem cell lines | journal = J. Biomed. Sci. | volume = 17 | issue = | pages = 64 | year = 2010 | pmid = 20670406 | pmc = 2923118 | doi = 10.1186/1423-0127-17-64 }}</ref><ref>{{cite journal |vauthors=Dashinimaev EB, Vishnyakova KS, Popov KV, Yegorov YE |title=Stable Culture of hTERT-transduced Human Embryonic Neural Stem Cells Holds All the Features of Primary Culture|journal= Electronic Journal of Biology | year = 2008 | volume = 4 | issue = 2 | pages = 93–97 | url = http://www.ejbio.com/pps/2008/93.pdf }}</ref><ref name="Elwood">{{cite journal |vauthors=Elwood NJ, Jiang XR, Chiu CP, Lebkowski JS, Smith CA | title = Enhanced long-term survival, but no increase in replicative capacity, following retroviral transduction of human cord blood CD34+ cells with human telomerase reverse transcriptase | journal = Haematologica | volume = 89 | issue = 3 | pages = 377–8 |date=March 2004 | pmid = 15020288 | doi = }}</ref>  hTERT over-expression increases the stem cell properties of human [[mesenchymal stem cells]].  The expression profile of mesenchymal stem cells converges towards embryonic stem cells, suggesting that these cells may have embryonic stem cell-like properties.  However, it has been observed that mesenchymal stem cells undergo decreased levels of spontaneous [[Differentiation (cellular)|differentiation]].<ref name="Tsai"/> This suggests that the differentiation capacity of adult stem cells may be dependent on telomerase activities. Therefore, over-expression of hTERT, which is akin to increasing telomerase activities, may create adult stem cells with a larger capacity for differentiation and hence, a larger capacity for treatment.
Increasing the telomerase activities in stem cells gives different effects depending on the intrinsic nature of the different types of stem cells.<ref name="Flores"/> Hence, not all stem cells will have increased stem-cell properties. For example, research has shown that telomerase can be upregulated in CD34+ [[Umbilical cord blood|Umbilical Cord Blood Cells]] through hTERT over-expression. The survival of these stem cells was enhanced, although there was no increase in the amount of population doubling.<ref name=Elwood/>
 
== Clinical significance ==
 
Deregulation of telomerase expression in somatic cells may be involved in [[oncogenesis]].<ref name="entrez"/>
 
Genome-wide association studies suggest TERT is a susceptibility gene for development of many cancers,<ref name="pmid20478107">{{cite journal | author = Baird DM | title = Variation at the TERT locus and predisposition for cancer | journal = Expert Rev Mol Med | volume = 12 | issue = | pages = e16 | year = 2010 | pmid = 20478107 | doi = 10.1017/S146239941000147X }}</ref> including lung cancer.<ref name="pmid18978790">{{cite journal  |vauthors=McKay JD, Hung RJ, Gaborieau V, Boffetta P, Chabrier A, Byrnes G, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, etal | title = Lung cancer susceptibility locus at 5p15.33 | journal = Nat. Genet. | volume = 40 | issue = 12 | pages = 1404–6 |date=December 2008 | pmid = 18978790 | pmc = 2748187 | doi = 10.1038/ng.254 }}</ref>
 
=== Role in cancer ===
 
[[Telomerase]] activity is associated with the number of times a cell can divide playing an important role in the immortality of cell lines, such as [[cancer cells]]. The [[enzyme]] complex acts through the addition of telomeric repeats to the ends of chromosomal DNA. This generates immortal cancer cells.<ref name="Sundin">{{cite journal |vauthors=Sundin T, Hentosh P | title = InTERTesting association between telomerase, mTOR and phytochemicals | journal = Expert Rev Mol Med | volume = 14 | issue = | pages = e8 | year = 2012 | pmid = 22455872 | doi = 10.1017/erm.2012.1 }}</ref> In fact, there is a strong correlation between telomerase activity and malignant [[tumors]] or cancerous cell lines.<ref name="Zhang">{{cite journal |vauthors=Zhang X, Mar V, Zhou W, Harrington L, Robinson MO | title = Telomere shortening and apoptosis in telomerase-inhibited human tumor cells | journal = Genes Dev. | volume = 13 | issue = 18 | pages = 2388–99 |date=September 1999 | pmid = 10500096 | pmc = 317024 | doi =  10.1101/gad.13.18.2388}}</ref> Not all types of human cancer have increased telomerase activity.  90% of cancers are characterized by increased telomerase activity.<ref name="Zhang"/> [[Lung cancer]] is the most well characterized type of cancer associated with telomerase.<ref name="Mocellin">{{cite journal |vauthors=Mocellin S, Verdi D, Pooley KA, Landi MT, Egan KM, Baird DM, Prescott J, De Vivo I, Nitti D | title = Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis | journal = J. Natl. Cancer Inst. | volume = 104 | issue = 11 | pages = 840–54 |date=June 2012 | pmid = 22523397 | doi = 10.1093/jnci/djs222 }}</ref> There is a lack of substantial telomerase activity in some cell types such as primary human [[fibroblasts]], which become [[Senescence|senescent]] after about 30–50 population doublings.<ref name=Zhang/> There is also evidence that telomerase activity is increased in tissues, such as [[germ cell]] lines, that are self-renewing. Normal [[somatic cells]], on the other hand, do not have detectable telomerase activity.<ref name=Glukhov>{{cite journal |vauthors=Glukhov AI, Svinareva LV, Severin SE, Shvets VI | title=Telomerase inhibitors as novel antitumour drugs | journal = Applied Biochemistry and Microbiology | volume=47 | pages = 655–660 | year = 2011 | doi = 10.1134/S0003683811070039 }}</ref> Since the catalytic component of telomerase is its reverse transcriptase, hTERT, and the RNA component hTERC, hTERT is an important [[gene]] to investigate in terms of cancer and [[tumorigenesis]].
The hTERT gene has been examined for [[mutation]]s and their association with the risk of contracting cancer. Over two hundred combinations of hTERT [[polymorphism (biology)|polymorphism]]s and cancer development have been found.<ref name=Mocellin/> There were several different types of cancer involved, and the strength of the correlation between the polymorphism and developing cancer varied from weak to strong.<ref name=Mocellin/> The regulation of hTERT has also been researched to determine possible mechanisms of telomerase activation in cancer cells.  Glycogen synthase kinase 3 ([[GSK3]]) seems to be over-expressed in most cancer cells.<ref name=Sundin/> GSK3 is involved in promoter activation through controlling a network of [[transcription factors]].<ref name=Sundin/> [[Leptin]] is also involved in increasing mRNA expression of hTERT via signal transducer and activation of transcription 3 ([[STAT3]]), proposing a mechanism for increased cancer incidence in obese individuals.<ref name=Sundin/> There are several other regulatory mechanisms that are altered or aberrant in cancer cells, including the [[Ras subfamily|Ras]] signaling pathway and other transcriptional regulators.<ref name=Sundin/> [[Phosphorylation]] is also a key process of post-transcriptional modification that regulates mRNA expression and cellular localization.<ref name=Sundin/> Clearly, there are many regulatory mechanisms of activation and repression of hTERT and telomerase activity in the cell, providing methods of immortalization in cancer cells.
 
=== Therapeutic potential ===
 
If increased [[telomerase]] activity is associated with [[malignancy]], then possible cancer treatments could involve inhibiting its catalytic component, hTERT, to reduce the enzyme’s activity and cause cell death. Since normal somatic cells do not express TERT, telomerase inhibition in cancer cells can cause senescence and [[apoptosis]] without affecting normal human cells.<ref name=Sundin/> It has been found that [[Dominant negative mutation|dominant-negative mutants]] of hTERT could reduce telomerase activity within the cell.<ref name=Zhang/> This led to apoptosis and cell death in cells with short [[telomere]] lengths, a promising result for cancer treatment.<ref name=Zhang/> Although cells with long telomeres did not experience apoptosis, they developed mortal characteristics and underwent telomere shortening.<ref name=Zhang/> Telomerase activity has also been found to be inhibited by [[phytochemicals]] such as [[isoprenoid]]s, [[genistein]], [[curcumin]], etc.<ref name=Sundin/> These chemicals play a role in inhibiting the [[mTOR]] pathway via [[down-regulation]] of phosphorylation.<ref name=Sundin/> The mTOR pathway is very important in regulating protein synthesis and it interacts with telomerase to increase its expression.<ref name=Sundin/> Several other chemicals have been found to inhibit telomerase activity and are currently being tested as potential clinical treatment options such as [[nucleoside analogues]], [[retinoic acid]] derivatives, [[quinolone antibiotics]], and [[Catechin|catechin derivatives]].<ref name=Glukhov/> There are also other molecular genetic-based methods of inhibiting telomerase, such as [[antisense therapy]] and [[RNA interference]].<ref name=Glukhov/>
 
hTERT [[peptide]] fragments have been shown to induce a [[cytotoxic T-cell]] reaction against telomerase-positive tumor cells ''[[in vitro]]''.<ref name="pmid10759561">{{cite journal |vauthors=Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M | title = Cytotoxic T cell immunity against telomerase reverse transcriptase in humans | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 9 | pages = 4796–801 |date=April 2000 | pmid = 10759561 | pmc = 18312 | doi = 10.1073/pnas.070560797 }}</ref> The response is mediated by [[dendritic cells]], which can display hTERT-associated [[antigens]] on [[Major histocompatibility complex|MHC]] class I and II receptors following [[adenoviral]] [[transduction (genetics)|transduction]] of an hTERT [[plasmid]] into dendritic cells, which mediate [[T-cell]] responses.<ref name="pmid12637945">{{cite journal |vauthors=Frolkis M, Fischer MB, Wang Z, Lebkowski JS, Chiu CP, Majumdar AS | title = Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors | journal = Cancer Gene Ther. | volume = 10 | issue = 3 | pages = 239–49 |date=March 2003 | pmid = 12637945 | doi = 10.1038/sj.cgt.7700563 }}</ref> Dendritic cells are then able to present telomerase-associated [[antigens]] even with undetectable amounts of telomerase activity, as long as the hTERT plasmid is present.<ref name="pmid10403642">{{cite journal |vauthors=Vonderheide RH, Hahn WC, Schultze JL, Nadler LM | title = The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes | journal = Immunity | volume = 10 | issue = 6 | pages = 673–9 |date=June 1999 | pmid = 10403642 | doi = 10.1016/S1074-7613(00)80066-7 }}</ref> [[Immunotherapy]] against telomerase-positive tumor cells is a promising field in cancer research that has been shown to be effective in ''[[in vitro]]'' and [[mouse model]] studies.<ref name="pmid10204484">{{cite journal | author = Rosenberg SA | title = A new era for cancer immunotherapy based on the genes that encode cancer antigens | journal = Immunity | volume = 10 | issue = 3 | pages = 281–7 |date=March 1999 | pmid = 10204484 | doi = 10.1016/S1074-7613(00)80028-X }}</ref>
 
== Medical implications ==
 
=== iPS cells ===
 
[[Induced pluripotent stem cells]] (iPS cells) are [[somatic (biology)|somatic]] cells that have been reprogrammed into a [[stem cell]]-like state by the introduction of four factors ([[Oct3/4]], [[Sox2]], [[Klf4]], and [[c-Myc]]).<ref name=Takahashi/>  iPS cells have the ability to self-renew indefinitely and contribute to all three [[germ layers]] when implanted into a [[blastocyst]] or use in [[teratoma]] formation.<ref name=Takahashi/>
 
Early development of iPS cell lines were not efficient, as they yielded up to 5% of somatic cells successfully reprogrammed into a stem cell-like state.<ref name="Utikal">{{cite journal |vauthors=Utikal J, Polo JM, Stadtfeld M, Maherali N, Kulalert W, Walsh RM, Khalil A, Rheinwald JG, Hochedlinger K | title = Immortalization eliminates a roadblock during cellular reprogramming into iPS cells | journal = Nature | volume = 460 | issue = 7259 | pages = 1145–8 |date=August 2009 | pmid = 19668190 | doi = 10.1038/nature08285  | pmc = 3987892 }}</ref>  By using [[Biological immortality|immortalized]] [[somatic (biology)|somatic]] cells ([[Differentiation (cellular)|differentiated]] cells with hTERT [[Upregulation|upregulated]]), iPS cell reprogramming was increased by twentyfold compared to reprogramming using [[wikt:mortal|mortal]] cells.<ref name=Utikal/>
 
The reactivation of hTERT, and subsequently [[telomerase]], in human iPS cells has been used as an indication of [[pluripotency]] and reprogramming to an [[Embryonic stem cell|ES]] (embryonic stem) cell-like state when using mortal cells.<ref name="Takahashi">{{cite journal |vauthors=Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–72 |date=November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 | url = }}</ref> Reprogrammed cells that do not express sufficient hTERT levels enter a [[G0 phase|quiescent]] state following a number of replications depending on the length of the telomeres while maintaining stem cell-like abilities to differentiate.<ref name=Utikal/> Reactivation of [[TERT]] activity can be achieved using only three of the four reprogramming factors described by Takahashi and Yamanaka: To be specific, [[Oct3/4]], [[Sox2]] and [[Klf4]] are essential, whereas [[c-Myc]] is not.<ref name="Marion">{{cite journal |vauthors=Marion RM, Strati K, Li H, Tejera A, Schoeftner S, Ortega S, Serrano M, Blasco MA | title = Telomeres acquire embryonic stem cell characteristics in induced pluripotent stem cells | journal = Cell Stem Cell | volume = 4 | issue = 2 | pages = 141–54 |date=February 2009 | pmid = 19200803 | doi = 10.1016/j.stem.2008.12.010 }}</ref> However, this study was done with cells containing [[endogenous]] levels of [[c-Myc]] that may have been sufficient for reprogramming.
 
Telomere length in healthy adult cells elongates and acquires epigenetic characteristics similar to those of [[Embryonic stem cell|ES cells]] when reprogrammed as iPS cells.  Some epigenetic characteristics of [[Embryonic stem cell|ES cells]] include a low density of tri-methylated [[histones]] H3K9 and H4K20 at telomeres, as well as an increased detectable amount of TERT [[Messenger RNA|transcripts]] and protein activity.<ref name=Marion /> Without the restoration of TERT and associated telomerase proteins, the efficiency of iPS cells would be drastically reduced.  iPS cells would also lose the ability to self-renew and would eventually [[Senescence|senesce]].<ref name=Marion/>
 
DKC ([[dyskeratosis congenita]]) patients are all characterized by the defective maintenance of [[telomeres]] leading to problems with [[stem cell]] regeneration.<ref name=Walne>{{cite journal |vauthors=Walne AJ, Dokal I | title=Advances in the understanding of dyskeratosis congenita | journal=[[British Journal of Haematology]] | volume=145 | pages=164–172 | year=2009 | doi=10.1111/j.1365-2141.2009.07598.x| pmc=2882229 }}</ref>  iPS cells derived from [[Dyskeratosis congenita|DKC]] patients with a [[heterozygous]] [[mutation]] on the TERT gene display a 50% reduction in telomerase activity compared to [[wild type]] iPS cells.<ref name=Batista>{{cite journal |vauthors=Batista LF, Pech MF, Zhong FL, Nguyen HN, Xie KT, Zaug AJ, Crary SM, Choi J, Sebastiano V, Cherry A, Giri N, Wernig M, Alter BP, Cech TR, Savage SA, Reijo Pera RA, Artandi SE | title=Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells | journal=[[Nature (journal)|Nature]] | volume=474 | issue=7351 | pages=399–402 | year=2011 | doi=10.1038/nature10084 | pmid=21602826 | pmc=3155806}}</ref> Conversely, mutations on the [[Telomerase RNA component|TERC]] gene (RNA portion of telomerase complex) can be overcome by [[up-regulation]] due to reprogramming as long as the hTERT gene is intact and functional.<ref>{{cite journal |vauthors=Agarwal S, Loh YH, McLoughlin EM, Huang J, Park IH, Miller JD, Huo H, Okuka M, Dos Reis RM, Loewer S, Ng HH, Keefe DL, Goldman FD, Klingelhutz AJ, Liu L, Daley GQ | title=Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients | journal=[[Nature (journal)|Nature]] | volume=464 | issue=7286 | pages=292–296 | year=2010 | doi=10.1038/nature08792 | pmid=20164838 | pmc=3058620}}</ref> Lastly, iPS cells generated with [[Dyskeratosis congenita|DKC]] cells with a mutated [[dyskerin]] (DKC1) gene cannot assemble the hTERT/RNA complex and thus do not have functional telomerase.<ref name=Batista/>
 
The functionality and efficiency of a reprogrammed iPS cell is determined by the ability of the cell to re-activate the telomerase complex and elongate its telomeres allowing for self-renewal.  hTERT is a major limiting component of the telomerase complex and a deficiency of intact hTERT impedes the activity of telomerase, making iPS cells an unsuitable pathway towards therapy for telomere-deficient disorders.<ref name=Batista />
 
=== Androgen therapy ===
 
Although the mechanism is not fully understood, exposure of TERT-deficient [[hematopoietic]] cells to [[androgens]] resulted in an increased level of TERT activity.<ref name=Calado/>  Cells with a [[heterozygous]] TERT mutation, like those in [[Dyskeratosis congenita|DKC (dyskeratosis congenita)]] patients, which normally exhibit low baseline levels of TERT, could be restored to normal levels comparable to control cells.  TERT [[mRNA]] levels are also increased with exposure to androgens.<ref name="Calado">{{cite journal |vauthors=Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS | title = Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells | journal = Blood | volume = 114 | issue = 11 | pages = 2236–43 |date=September 2009 | pmid = 19561322 | pmc = 2745844 | doi = 10.1182/blood-2008-09-178871 }}</ref>  Androgen therapy may become a suitable method for treating circulatory ailments such as [[bone marrow]] degeneration and low blood count linked with [[Dyskeratosis congenita|DKC]] and other telomerase-deficient conditions.<ref name=Calado/>
 
=== Aging ===
 
As organisms age and cells proliferate, telomeres shorten with each round of replication.  Cells restricted to a specific lineage are capable of division only a set number of times, set by the length of telomeres, before they [[Senescence|senesce]].<ref name="Sahin">{{cite journal |vauthors=Sahin E, Depinho RA | title = Linking functional decline of telomeres, mitochondria and stem cells during ageing | journal = Nature | volume = 464 | issue = 7288 | pages = 520–8 |date=March 2010 | pmid = 20336134 | doi = 10.1038/nature08982 | pmc = 3733214 }}</ref>  Depletion and uncapping of telomeres has been linked to organ degeneration, [[Organ failure|failure]], and [[fibrosis]] due to progenitors' becoming [[G0 phase|quiescent]] and unable to [[Differentiate (cellular)|differentiate]].<ref name=Flores2 /><ref name=Sahin /> Using an ''[[in vivo]]'' TERT deficient [[mouse model]], reactivation of the TERT gene in [[G0 phase|quiescent]] populations in multiple organs reactivated telomerase and restored the cells’ abilities to [[Differentiate (cellular)|differentiate]].<ref name="Jaskelioff">{{cite journal |vauthors=Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams AC, Sahin E, Kost-Alimova M, Protopopov A, Cadiñanos J, Horner JW, Maratos-Flier E, Depinho RA | title = Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice | journal = Nature | volume = 469 | issue = 7328 | pages = 102–6 |date=January 2011 | pmid = 21113150 | pmc = 3057569 | doi = 10.1038/nature09603 }}</ref>  Reactivation of TERT [[down-regulate]]s DNA damage signals associated with [[Cell cycle checkpoint|cellular mitotic checkpoints]] allowing for proliferation and elimination of a degenerative [[phenotype]].<ref name=Jaskelioff /> In another study, introducing the TERT gene into healthy one-year-old mice using an engineered [[adeno-associated virus]] led to a 24% increase in lifespan, without any increase in cancer.<ref name="pmid22585399">{{cite journal |vauthors=Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA | title = Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer | journal = EMBO Molecular Medicine | volume = 4 | issue = 8 | pages = 691–704 |date=August 2012 | pmid = 22585399 | pmc = 3494070 | doi = 10.1002/emmm.201200245 }}</ref>
 
===Relation to epigenetic clock===
Paradoxically, genetic variants in the TERT locus, which are associated with longer leukocyte telomere length,
are associated with faster epigenetic aging rates in blood according to a molecular biomarker of aging known as [[epigenetic clock]].<ref name="LuGWAS2018">{{cite journal | vauthors = Lu AT, Xue L, Salfati EL, Chen BH, Ferrucci L, Levy D, Joehanes R, Murabito JM, Kiel DP, Tsai PC, Yet I, Bell JT, Mangino M, Tanaka T, McRae AF, Marioni RE, Visscher PM, Wray NR, Deary IJ, Levine ME, Quach A, Assimes T, Tsao PS, Absher D, Stewart JD, Li Y, Reiner AP, Hou L, Baccarelli AA, Whitsel EA, Aviv A, Cardona A, Day FR, Wareham NJ, Perry JR, Ong KK, Raj K, Lunetta KL, Horvath S | display-authors = 6 | title = GWAS of epigenetic aging rates in blood reveals a critical role for TERT | journal = Nature Communications | volume = 9 | issue = 1 | pages = 387 | date = January 2018 | pmid = 29374233 | pmc = 5786029 | doi = 10.1038/s41467-017-02697-5 }}</ref> Similarly, human TERT expression did not arrest epigenetic aging in human fibroblasts. <ref name="LuGWAS2018"/>
 
=== Gene therapy ===
The hTERT [[gene]] has become a main focus for gene therapy involving cancer due to its expression in [[tumor]] cells but not [[Somatic (biology)|somatic]] adult cells.<ref name=Abdul>{{cite journal |vauthors=Abdul-Ghani R, Ohana P, Matouk I, Ayesh S, Ayesh B, Laster M, Bibi O, Giladi H, Molnar-Kimber K, Sughayer MA, de Groot N, Hochberg A | title = Use of transcriptional regulatory sequences of telomerase (hTER and hTERT) for selective killing of cancer cells | journal = Mol. Ther. | volume = 2 | issue = 6 | pages = 539–44 |date=December 2000 | pmid = 11124054 | doi = 10.1006/mthe.2000.0196 }}</ref>  One method is to prevent the [[Translation (biology)|translation]] of hTERT [[mRNA]] through the introduction of [[siRNA]], which are complimentary sequences that bind to the mRNA preventing processing of the gene post [[transcription (genetics)|transcription]].<ref name=Zhang2>{{cite journal |vauthors=Zhang PH, Tu ZG, Yang MQ, Huang WF, Zou L, Zhou YL | title = [Experimental research of targeting hTERT gene inhibited in hepatocellular carcinoma therapy by RNA interference] | language = Chinese | journal = Ai Zheng | volume = 23 | issue = 6 | pages = 619–25 |date=June 2004 | pmid = 15191658 | doi =  }}</ref>  This method does not completely eliminate [[telomerase]] activity, but it does lower telomerase activity and levels of hTERT mRNA seen in the [[cytoplasm]].<ref name=Zhang2/>  Higher success rates were seen ''in vitro'' when combining the use of antisense hTERT sequences with the introduction of a tumor-suppressing [[plasmid]] by [[adenovirus]] infection such as [[PTEN (gene)|PTEN]].<ref name="pmid17310280">{{cite journal |vauthors=You Y, Geng X, Zhao P, Fu Z, Wang C, Chao S, Liu N, Lu A, Gardner K, Pu P, Kong C, Ge Y, Judge SI, Li QQ | title = Evaluation of combination gene therapy with PTEN and antisense hTERT for malignant glioma in vitro and xenografts | journal = Cell. Mol. Life Sci. | volume = 64 | issue = 5 | pages = 621–31 |date=March 2007 | pmid = 17310280 | doi = 10.1007/s00018-007-6424-4 }}</ref>
 
Another method that has been studied is manipulating the hTERT promoter to induce [[apoptosis]] in tumor cells.  Plasmid DNA sequences can be manufactured using the hTERT promoter followed by genes encoding for specific proteins.  The protein can be a toxin, an apoptotic factor, or a viral protein.  Toxins such as [[diphtheria]] toxin interfere with cellular processes and eventually induce apoptosis.<ref name=Abdul/>  Apoptotic death factors like [[FADD]] (Fas-Associated protein with Death Domain) can be used to force cells expressing hTERT to undergo apoptosis.<ref name=Koga>{{cite journal |vauthors=Koga S, Hirohata S, Kondo Y, Komata T, Takakura M, Inoue M, Kyo S, Kondo S | title = FADD gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter to restrict induction of apoptosis to tumors in vitro and in vivo | journal = Anticancer Res. | volume = 21 | issue = 3B | pages = 1937–43 | year = 2001 | pmid = 11497281 | doi = }}</ref> Viral proteins like viral [[thymidine kinase]] can be used for specific targeting of a drug.<ref name=Song>{{cite journal |vauthors=Song JS, Kim HP, Yoon WS, Lee KW, Kim MH, Kim KT, Kim HS, Kim YT | title = Adenovirus-mediated suicide gene therapy using the human telomerase catalytic subunit (hTERT) gene promoter induced apoptosis of ovarian cancer cell line | journal = Biosci. Biotechnol. Biochem. | volume = 67 | issue = 11 | pages = 2344–50 |date=November 2003 | pmid = 14646192 | doi = 10.1271/bbb.67.2344}}</ref> By introducing a prodrug only activated by the viral enzyme, specific targeting of cells expressing hTERT can be achieved.<ref name=Song/>  By using the hTERT promoter, only cells expressing hTERT will be affected and allows for specific targeting of tumor cells.<ref name=Abdul/><ref name=Koga/><ref name=Song/>
 
Aside from cancer therapies, the hTERT gene has been used to promote the growth of hair follicles.<ref name="pmid21593794">{{cite journal |vauthors=Jan HM, Wei MF, Peng CL, Lin SJ, Lai PS, Shieh MJ | title = The use of polyethylenimine-DNA to topically deliver hTERT to promote hair growth | journal = Gene Ther. | volume = 19 | issue = 1 | pages = 86–93 |date=January 2012 | pmid = 21593794 | doi = 10.1038/gt.2011.62 }}</ref>
 
A schematic animation for gene therapy is shown as follows.
 
[[File:HTERT Final gif.gif|center|HTERT Final gif]]
 
== Interactions ==
 
Telomerase reverse transcriptase has been shown to [[Protein-protein interaction|interact]] with:
* [[Heat shock protein 90kDa alpha (cytosolic), member A1|HSP90AA1]],<ref name="pmid12586360">{{cite journal |vauthors=Haendeler J, Hoffmann J, Rahman S, Zeiher AM, Dimmeler S | title = Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation | journal = FEBS Lett. | volume = 536 | issue = 1-3 | pages = 180–6 |date=February 2003 | pmid = 12586360 | doi = 10.1016/S0014-5793(03)00058-9 }}</ref><ref name="pmid15843522">{{cite journal |vauthors=Kawauchi K, Ihjima K, Yamada O | title = IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells | journal = J. Immunol. | volume = 174 | issue = 9 | pages = 5261–9 |date=May 2005 | pmid = 15843522 | doi = 10.4049/jimmunol.174.9.5261}}</ref>
* [[Ku70]],<ref name="pmid12377759">{{cite journal |vauthors=Chai W, Ford LP, Lenertz L, Wright WE, Shay JW | title = Human Ku70/80 associates physically with telomerase through interaction with hTERT | journal = J. Biol. Chem. | volume = 277 | issue = 49 | pages = 47242–7 |date=December 2002 | pmid = 12377759 | doi = 10.1074/jbc.M208542200  }}</ref>
* [[Ku80]],<ref name=pmid12377759/>
* [[MCRS1]],<ref name="pmid15044100">{{cite journal |vauthors=Song H, Li Y, Chen G, Xing Z, Zhao J, Yokoyama KK, Li T, Zhao M | title = Human MCRS2, a cell-cycle-dependent protein, associates with LPTS/PinX1 and reduces the telomere length | journal = Biochem. Biophys. Res. Commun. | volume = 316 | issue = 4 | pages = 1116–23 |date=April 2004 | pmid = 15044100 | doi = 10.1016/j.bbrc.2004.02.166 | url = }}</ref>
* [[Nucleolin]],<ref name="pmid15371412">{{cite journal |vauthors=Khurts S, Masutomi K, Delgermaa L, Arai K, Oishi N, Mizuno H, Hayashi N, Hahn WC, Murakami S | title = Nucleolin interacts with telomerase | journal = J. Biol. Chem. | volume = 279 | issue = 49 | pages = 51508–15 |date=December 2004 | pmid = 15371412 | doi = 10.1074/jbc.M407643200 }}</ref>
* [[PINX1]],<ref name="pmid11701125">{{cite journal |vauthors=Zhou XZ, Lu KP | title = The Pin2/TRF1-interacting protein PinX1 is a potent telomerase inhibitor | journal = Cell | volume = 107 | issue = 3 | pages = 347–59 |date=November 2001 | pmid = 11701125 | doi = 10.1016/S0092-8674(01)00538-4 }}</ref> and
* [[YWHAQ]].<ref name="pmid10835362">{{cite journal |vauthors=Seimiya H, Sawada H, Muramatsu Y, Shimizu M, Ohko K, Yamane K, Tsuruo T | title = Involvement of 14-3-3 proteins in nuclear localization of telomerase | journal = EMBO J. | volume = 19 | issue = 11 | pages = 2652–61 |date=June 2000 | pmid = 10835362 | pmc = 212742 | doi = 10.1093/emboj/19.11.2652 | url = }}</ref>


==See also==
==See also==
* [[telomerase]]
* [[telomerase]]
* [[reverse transcriptase]]
* [[reverse transcriptase]]
{{clear}}
==References==
{{Reflist|35em}}
==Further reading==
{{Refbegin|35em}}
*{{cite journal  |vauthors=Mattson MP, Fu W, Zhang P |title=Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective |journal=Mech. Ageing Dev. |volume=122 |issue= 7 |pages= 659–71 |year= 2001 |pmid= 11322991 |doi=10.1016/S0047-6374(01)00221-4  }}
*{{cite journal  |vauthors=Castillo Ureta H, Barrera Saldaña HA, Martínez Rodríguez HG |title=[Telomerase: an enzyme with multiple applications in cancer research] |journal=Rev. Invest. Clin. |volume=54 |issue= 4 |pages= 342–8 |year= 2003 |pmid= 12415959 |doi=  }}
*{{cite journal  | author=Janknecht R |title=On the road to immortality: hTERT upregulation in cancer cells |journal=FEBS Lett. |volume=564 |issue= 1–2 |pages= 9–13 |year= 2004 |pmid= 15094035 |doi= 10.1016/S0014-5793(04)00356-4 }}
*{{cite journal  |vauthors=Cristofari G, Sikora K, Lingner J |title=Telomerase unplugged |journal=ACS Chem. Biol. |volume=2 |issue= 3 |pages= 155–8 |year= 2007 |pmid= 17373762 |doi= 10.1021/cb700037c }}
*{{cite journal  |vauthors=Beliveau A, Yaswen P |title=Soothing the watchman: telomerase reduces the p53-dependent cellular stress response |journal=Cell Cycle |volume=6 |issue= 11 |pages= 1284–7 |year= 2007 |pmid= 17534147 |doi=10.4161/cc.6.11.4298  }}
*{{cite journal  |vauthors=Bellon M, Nicot C |title=Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia |journal=Cancer genomics & proteomics |volume=4 |issue= 1 |pages= 21–5 |year= 2007 |pmid= 17726237 |doi=  }}
{{Refend}}


==External links==
==External links==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dkc  GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pf  GeneReviews/NCBI/NIH/UW entry on Pulmonary Fibrosis, Familial]
* {{MeshName|TERT+protein,+human}}
* {{MeshName|TERT+protein,+human}}


{{biochem-stub}}
{{Kinases}}
{{WikiDoc Sources}}
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[[Category:Telomeres]]

Latest revision as of 18:12, 31 July 2018

For the chemical descripter, see Descriptor_(Chemistry) § sec-,_tert-.
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Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.[1][2]

Telomerases are part of a distinct subgroup of RNA-dependent polymerases. Telomerase lengthens telomeres in DNA strands, thereby allowing senescent cells that would otherwise become postmitotic and undergo apoptosis to exceed the Hayflick limit and become potentially immortal, as is often the case with cancerous cells. To be specific, TERT is responsible for catalyzing the addition of nucleotides in a TTAGGG sequence to the ends of a chromosome’s telomeres.[3] This addition of repetitive DNA sequences prevents degradation of the chromosomal ends following multiple rounds of replication.[4]

hTERT absence (usually as a result of a chromosomal mutation) is associated with the disorder Cri du chat.[5][6]

Function

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells, resulting in progressive shortening of telomeres. Studies in mice suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity.[7]

Regulation of hTERT

The hTERT gene, located on chromosome 5, consists of 16 exons and 15 introns spanning 35 kb. The core promoter of hTERT includes 330 base pairs upstream of the translation start site (AUG since it's RNA by using the words "exons" and "introns"), as well as 37 base pairs of exon 2 of the hTERT gene.[8][9][10] The hTERT promoter is GC-rich and lacks TATA and CAAT boxes but contains many sites for several transcription factors giving indication of a high level of regulation by multiple factors in many cellular contexts.[8] Transcription factors that can activate hTERT include many oncogenes (cancer-causing genes) such as c-Myc, Sp1, HIF-1, AP2, and many more, while many cancer suppressing genes such as p53, WT1, and Menin produce factors that suppress hTERT activity .[10][11] Another form of up-regulation is through demethylation of histones proximal to the promoter region, imitating the low density of trimethylated histones seen in embryonic stem cells.[12] This allows for the recruitment of histone acetyltransferase (HAT) to unwind the sequence allowing for transcription of the gene.[11]

Telomere deficiency is often linked to aging, cancers and the conditions dyskeratosis congenita (DKC) and Cri du chat. Meanwhile, over-expression of hTERT is often associated with cancers and tumor formation.[5][13][14][15] The regulation of hTERT is extremely important to the maintenance of stem and cancer cells and can be used in multiple ways in the field of regenerative medicine.

Stem cells

hTERT in stem cells

hTERT is often up-regulated in cells that divide rapidly, including both embryonic stem cells and adult stem cells.[14] It elongates the telomeres of stem cells, which, as a consequence, increases the lifespan of the stem cells by allowing for indefinite division without shortening of telomeres. Therefore, it is responsible for the self-renewal properties of stem cells. Telomerase are found specifically to target shorter telomere over longer telomere, due to various regulatory mechanisms inside the cells that reduce the affinity of telomerase to longer telomeres. This preferential affinity maintains a balance within the cell such that the telomeres are of sufficient length for their function and yet, at the same time, not contribute to aberrant telomere elongation [16]

High expression of hTERT is also often used as a landmark for pluripotency and multipotency state of embryonic and adult stem cells. Over-expression of hTERT was found to immortalize certain cell types as well as impart different interesting properties to different stem cells.[10][17]

Immortalization

hTERT immortalizes various normal cells in culture, thereby endowing the self-renewal properties of stem cells to non-stem cell cultures.[10][18] There are multiple ways in which immortalization of non-stem cells can be achieved, one of which being via the introduction of hTERT into the cells. Differentiated cells often express hTERC and TP1, a telomerase-associated protein that helps form the telomerase assembly, but does not express hTERT. Hence, hTERT acts as the limiting factor for telomerase activity in differentiated cells [10][19] However, with hTERT over-expression, active telomerase can be formed in differentiated cells. This method has been used to immortalize prostate epithelial and stromal-derived cells, which are typically difficult to culture in vitro. hTERT introduction allows in vitro culture of these cells and available for possible future research. hTERT introduction have an advantage over the use of viral protein for immortalization in that it does not involve the inactivation of tumor suppressor gene, which might lead to cancer formation.[18]

Enhancement of stem cell properties

Over-expression of hTERT in stem cells changes the properties of the cells.[17][20][21] hTERT over-expression increases the stem cell properties of human mesenchymal stem cells. The expression profile of mesenchymal stem cells converges towards embryonic stem cells, suggesting that these cells may have embryonic stem cell-like properties. However, it has been observed that mesenchymal stem cells undergo decreased levels of spontaneous differentiation.[17] This suggests that the differentiation capacity of adult stem cells may be dependent on telomerase activities. Therefore, over-expression of hTERT, which is akin to increasing telomerase activities, may create adult stem cells with a larger capacity for differentiation and hence, a larger capacity for treatment.

Increasing the telomerase activities in stem cells gives different effects depending on the intrinsic nature of the different types of stem cells.[14] Hence, not all stem cells will have increased stem-cell properties. For example, research has shown that telomerase can be upregulated in CD34+ Umbilical Cord Blood Cells through hTERT over-expression. The survival of these stem cells was enhanced, although there was no increase in the amount of population doubling.[21]

Clinical significance

Deregulation of telomerase expression in somatic cells may be involved in oncogenesis.[7]

Genome-wide association studies suggest TERT is a susceptibility gene for development of many cancers,[22] including lung cancer.[23]

Role in cancer

Telomerase activity is associated with the number of times a cell can divide playing an important role in the immortality of cell lines, such as cancer cells. The enzyme complex acts through the addition of telomeric repeats to the ends of chromosomal DNA. This generates immortal cancer cells.[24] In fact, there is a strong correlation between telomerase activity and malignant tumors or cancerous cell lines.[25] Not all types of human cancer have increased telomerase activity. 90% of cancers are characterized by increased telomerase activity.[25] Lung cancer is the most well characterized type of cancer associated with telomerase.[26] There is a lack of substantial telomerase activity in some cell types such as primary human fibroblasts, which become senescent after about 30–50 population doublings.[25] There is also evidence that telomerase activity is increased in tissues, such as germ cell lines, that are self-renewing. Normal somatic cells, on the other hand, do not have detectable telomerase activity.[27] Since the catalytic component of telomerase is its reverse transcriptase, hTERT, and the RNA component hTERC, hTERT is an important gene to investigate in terms of cancer and tumorigenesis.

The hTERT gene has been examined for mutations and their association with the risk of contracting cancer. Over two hundred combinations of hTERT polymorphisms and cancer development have been found.[26] There were several different types of cancer involved, and the strength of the correlation between the polymorphism and developing cancer varied from weak to strong.[26] The regulation of hTERT has also been researched to determine possible mechanisms of telomerase activation in cancer cells. Glycogen synthase kinase 3 (GSK3) seems to be over-expressed in most cancer cells.[24] GSK3 is involved in promoter activation through controlling a network of transcription factors.[24] Leptin is also involved in increasing mRNA expression of hTERT via signal transducer and activation of transcription 3 (STAT3), proposing a mechanism for increased cancer incidence in obese individuals.[24] There are several other regulatory mechanisms that are altered or aberrant in cancer cells, including the Ras signaling pathway and other transcriptional regulators.[24] Phosphorylation is also a key process of post-transcriptional modification that regulates mRNA expression and cellular localization.[24] Clearly, there are many regulatory mechanisms of activation and repression of hTERT and telomerase activity in the cell, providing methods of immortalization in cancer cells.

Therapeutic potential

If increased telomerase activity is associated with malignancy, then possible cancer treatments could involve inhibiting its catalytic component, hTERT, to reduce the enzyme’s activity and cause cell death. Since normal somatic cells do not express TERT, telomerase inhibition in cancer cells can cause senescence and apoptosis without affecting normal human cells.[24] It has been found that dominant-negative mutants of hTERT could reduce telomerase activity within the cell.[25] This led to apoptosis and cell death in cells with short telomere lengths, a promising result for cancer treatment.[25] Although cells with long telomeres did not experience apoptosis, they developed mortal characteristics and underwent telomere shortening.[25] Telomerase activity has also been found to be inhibited by phytochemicals such as isoprenoids, genistein, curcumin, etc.[24] These chemicals play a role in inhibiting the mTOR pathway via down-regulation of phosphorylation.[24] The mTOR pathway is very important in regulating protein synthesis and it interacts with telomerase to increase its expression.[24] Several other chemicals have been found to inhibit telomerase activity and are currently being tested as potential clinical treatment options such as nucleoside analogues, retinoic acid derivatives, quinolone antibiotics, and catechin derivatives.[27] There are also other molecular genetic-based methods of inhibiting telomerase, such as antisense therapy and RNA interference.[27]

hTERT peptide fragments have been shown to induce a cytotoxic T-cell reaction against telomerase-positive tumor cells in vitro.[28] The response is mediated by dendritic cells, which can display hTERT-associated antigens on MHC class I and II receptors following adenoviral transduction of an hTERT plasmid into dendritic cells, which mediate T-cell responses.[29] Dendritic cells are then able to present telomerase-associated antigens even with undetectable amounts of telomerase activity, as long as the hTERT plasmid is present.[30] Immunotherapy against telomerase-positive tumor cells is a promising field in cancer research that has been shown to be effective in in vitro and mouse model studies.[31]

Medical implications

iPS cells

Induced pluripotent stem cells (iPS cells) are somatic cells that have been reprogrammed into a stem cell-like state by the introduction of four factors (Oct3/4, Sox2, Klf4, and c-Myc).[32] iPS cells have the ability to self-renew indefinitely and contribute to all three germ layers when implanted into a blastocyst or use in teratoma formation.[32]

Early development of iPS cell lines were not efficient, as they yielded up to 5% of somatic cells successfully reprogrammed into a stem cell-like state.[33] By using immortalized somatic cells (differentiated cells with hTERT upregulated), iPS cell reprogramming was increased by twentyfold compared to reprogramming using mortal cells.[33]

The reactivation of hTERT, and subsequently telomerase, in human iPS cells has been used as an indication of pluripotency and reprogramming to an ES (embryonic stem) cell-like state when using mortal cells.[32] Reprogrammed cells that do not express sufficient hTERT levels enter a quiescent state following a number of replications depending on the length of the telomeres while maintaining stem cell-like abilities to differentiate.[33] Reactivation of TERT activity can be achieved using only three of the four reprogramming factors described by Takahashi and Yamanaka: To be specific, Oct3/4, Sox2 and Klf4 are essential, whereas c-Myc is not.[12] However, this study was done with cells containing endogenous levels of c-Myc that may have been sufficient for reprogramming.

Telomere length in healthy adult cells elongates and acquires epigenetic characteristics similar to those of ES cells when reprogrammed as iPS cells. Some epigenetic characteristics of ES cells include a low density of tri-methylated histones H3K9 and H4K20 at telomeres, as well as an increased detectable amount of TERT transcripts and protein activity.[12] Without the restoration of TERT and associated telomerase proteins, the efficiency of iPS cells would be drastically reduced. iPS cells would also lose the ability to self-renew and would eventually senesce.[12]

DKC (dyskeratosis congenita) patients are all characterized by the defective maintenance of telomeres leading to problems with stem cell regeneration.[13] iPS cells derived from DKC patients with a heterozygous mutation on the TERT gene display a 50% reduction in telomerase activity compared to wild type iPS cells.[34] Conversely, mutations on the TERC gene (RNA portion of telomerase complex) can be overcome by up-regulation due to reprogramming as long as the hTERT gene is intact and functional.[35] Lastly, iPS cells generated with DKC cells with a mutated dyskerin (DKC1) gene cannot assemble the hTERT/RNA complex and thus do not have functional telomerase.[34]

The functionality and efficiency of a reprogrammed iPS cell is determined by the ability of the cell to re-activate the telomerase complex and elongate its telomeres allowing for self-renewal. hTERT is a major limiting component of the telomerase complex and a deficiency of intact hTERT impedes the activity of telomerase, making iPS cells an unsuitable pathway towards therapy for telomere-deficient disorders.[34]

Androgen therapy

Although the mechanism is not fully understood, exposure of TERT-deficient hematopoietic cells to androgens resulted in an increased level of TERT activity.[36] Cells with a heterozygous TERT mutation, like those in DKC (dyskeratosis congenita) patients, which normally exhibit low baseline levels of TERT, could be restored to normal levels comparable to control cells. TERT mRNA levels are also increased with exposure to androgens.[36] Androgen therapy may become a suitable method for treating circulatory ailments such as bone marrow degeneration and low blood count linked with DKC and other telomerase-deficient conditions.[36]

Aging

As organisms age and cells proliferate, telomeres shorten with each round of replication. Cells restricted to a specific lineage are capable of division only a set number of times, set by the length of telomeres, before they senesce.[37] Depletion and uncapping of telomeres has been linked to organ degeneration, failure, and fibrosis due to progenitors' becoming quiescent and unable to differentiate.[16][37] Using an in vivo TERT deficient mouse model, reactivation of the TERT gene in quiescent populations in multiple organs reactivated telomerase and restored the cells’ abilities to differentiate.[38] Reactivation of TERT down-regulates DNA damage signals associated with cellular mitotic checkpoints allowing for proliferation and elimination of a degenerative phenotype.[38] In another study, introducing the TERT gene into healthy one-year-old mice using an engineered adeno-associated virus led to a 24% increase in lifespan, without any increase in cancer.[39]

Relation to epigenetic clock

Paradoxically, genetic variants in the TERT locus, which are associated with longer leukocyte telomere length, are associated with faster epigenetic aging rates in blood according to a molecular biomarker of aging known as epigenetic clock.[40] Similarly, human TERT expression did not arrest epigenetic aging in human fibroblasts. [40]

Gene therapy

The hTERT gene has become a main focus for gene therapy involving cancer due to its expression in tumor cells but not somatic adult cells.[41] One method is to prevent the translation of hTERT mRNA through the introduction of siRNA, which are complimentary sequences that bind to the mRNA preventing processing of the gene post transcription.[42] This method does not completely eliminate telomerase activity, but it does lower telomerase activity and levels of hTERT mRNA seen in the cytoplasm.[42] Higher success rates were seen in vitro when combining the use of antisense hTERT sequences with the introduction of a tumor-suppressing plasmid by adenovirus infection such as PTEN.[43]

Another method that has been studied is manipulating the hTERT promoter to induce apoptosis in tumor cells. Plasmid DNA sequences can be manufactured using the hTERT promoter followed by genes encoding for specific proteins. The protein can be a toxin, an apoptotic factor, or a viral protein. Toxins such as diphtheria toxin interfere with cellular processes and eventually induce apoptosis.[41] Apoptotic death factors like FADD (Fas-Associated protein with Death Domain) can be used to force cells expressing hTERT to undergo apoptosis.[44] Viral proteins like viral thymidine kinase can be used for specific targeting of a drug.[45] By introducing a prodrug only activated by the viral enzyme, specific targeting of cells expressing hTERT can be achieved.[45] By using the hTERT promoter, only cells expressing hTERT will be affected and allows for specific targeting of tumor cells.[41][44][45]

Aside from cancer therapies, the hTERT gene has been used to promote the growth of hair follicles.[46]

A schematic animation for gene therapy is shown as follows.

HTERT Final gif
HTERT Final gif

Interactions

Telomerase reverse transcriptase has been shown to interact with:

See also

References

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Further reading

  • Mattson MP, Fu W, Zhang P (2001). "Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective". Mech. Ageing Dev. 122 (7): 659–71. doi:10.1016/S0047-6374(01)00221-4. PMID 11322991.
  • Castillo Ureta H, Barrera Saldaña HA, Martínez Rodríguez HG (2003). "[Telomerase: an enzyme with multiple applications in cancer research]". Rev. Invest. Clin. 54 (4): 342–8. PMID 12415959.
  • Janknecht R (2004). "On the road to immortality: hTERT upregulation in cancer cells". FEBS Lett. 564 (1–2): 9–13. doi:10.1016/S0014-5793(04)00356-4. PMID 15094035.
  • Cristofari G, Sikora K, Lingner J (2007). "Telomerase unplugged". ACS Chem. Biol. 2 (3): 155–8. doi:10.1021/cb700037c. PMID 17373762.
  • Beliveau A, Yaswen P (2007). "Soothing the watchman: telomerase reduces the p53-dependent cellular stress response". Cell Cycle. 6 (11): 1284–7. doi:10.4161/cc.6.11.4298. PMID 17534147.
  • Bellon M, Nicot C (2007). "Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia". Cancer genomics & proteomics. 4 (1): 21–5. PMID 17726237.

External links

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