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Telomerase activity and telomere on stem progeny senescence
Biomedicine & Pharmacotherapy 102 (2018) 9–17
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Telomerase activity and telomere on stem progeny senescence a
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Balal Brazvan , Abbas Ebrahimi-Kalan , Kobra Velaei , Ahmad Mehdipour , ⁎ Zeynab Aliyari serejf,i, Ayyub Ebrahimig, Mohammad Ghorbania, Omid Cheraghih, , j,⁎ Hojjatollah Nozad Charoudeh a
Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran c Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran e Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Applied Cell Sciences Department, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran g Department of Molecular Biology and Genetic, Faculty of Arts and Sciences, Halic Uuniversity, Istanbul, Turkey h Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran i Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran j Drug Applied research center, Tabriz University of Medical Sciences, Tabriz, Iran b
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Keywords: Telomere Telomerase Hematopoietic stem cells Cytokine
The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme. Human Telomerase Reverse Transcriptase (hTERT) gene expression plays an important role in maintaining telomere length and high proliferative property of cells. Except a low activity of telomerase enzyme in hematopoietic and few types of stem cells, most of somatic cells didn’t showed telomerase activity. Moreover, cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation. Also, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. In this review we have tried to talk about effects of immune cell cytokines on telomerase expression/telomere length and the induction of telomerase expression by cytokines.
1. History of telomere study The telomere was described, for the first time, as a protective structure at the end of the chromosomes in 1930 by Hermann J. Muller and Barbara McClintock to prevent the end-to-end fusion that may occur in the chromosomes and lead to cell death [1]. In 1960, Hayflick described a biological view of aging. He concluded that human diploid cells indicating a limitation in proliferation and Hayflick’s limit is considered to be the maximum number of cell divisions [2,3]. In 1970, James D. Watson defined the End Replication Problem during DNA replication. Indeed DNA polymerase couldn’t completely replicate the end of the 5' chromosome [4]. Then, in 1973, Olovnikov linked the cell senescence with the end replication problem in the "Theory of Marginotomy". In this theory, telomere shortening was considered as an
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internal hourly mechanism of aging. later in 1980 this theory had approved and they observed the shortening of telomere length during in vitro cell proliferation conditions [5]. Elizabeth Blackburn found that the molecular structure of Tetrahymena pyriformis telomeres has a rich of guanine (G) and thymine (T) nucleotide [6] and in 1984 Elizabeth Blackburn et al. isolated an enzyme that called telomerase. They proved, this enzyme is responsible for telomere length regulation and later reported that the presence of telomerase activity in human cancer cells have led to the immortality of these cells [7]. This is true that telomerase enzyme is not alone in telomere length regulation and another mechanism such as alternative telomere length has an important [8] and telomere and telomerase have been studied extensively because of its important role in physiologic aging, cancer pathology and premature aging syndrome.
Corresponding authors. E-mail addresses: [email protected] (O. Cheraghi), [email protected] (H. Nozad Charoudeh).
https://doi.org/10.1016/j.biopha.2018.02.073 Received 31 December 2017; Received in revised form 3 February 2018; Accepted 19 February 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
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2. Telomere structure
(TCAB1) is another protein that binds to the enzyme and adjusts its transit [42]. In vertebrates, the RNA that transmitted by telomerase enzyme has about 382–559 nucleotides [43]. The number of RNA nucleotides transmitted by the human telomerase enzyme is about 451 nucleotides and its nucleotide sequence composed of 5'-CUAACCCU AAC-3' sequences, which is responsible for coding the telomere sequences [44] (Fig. 2).
The ends of linear chromosomes have been formed with a special heterochromatin structure that called telomere and this structure protect the end of the chromosome from degradation and act as DNA repair mechanism, therefore, the telomere is a structure that is essential for the stability of the chromosome [9,10]. The mammalian telomeres consist of several kilobases, for example, telomere length in humans is 10–15 kb and 25–50 kb in mice that consisting of repetitive TTAGGG sequences [1,11,12]. This specific rich region of guanine structure is characterized by the presence of 30–400 nucleotides at the end of the 3′ chromosome [13,14]. Telomeres are linked to specific structures that called Shelterin, which is essential for telomere length regulation, telomere protection from the DNA damage response system and keep the chromosome end of the DNA repair machine [15]. The Shelterin Complex consists of six central proteins; TRF1 (telomeric repeat binding factor 1), TRF2 (telomeric repeat binding factor 2), TIN2 (TRF1-interacting protein 2), POT1 (protection of telomeres protein 1), TPP1 (TIN2- and POT1-interacting protein) and RAP1 (repressor/activator protein 1) [16–19]. Homodimers of TRF1 and TRF2 bind to doublestrand telomeric DNA in one side and TIN2 on the other side which form Shelterin core complex [20]. Other proteins such POT1 binds to single strand telomeric DNA sequence [21,22]. TIN2 binds to TRF1 and TRF2 and acts as a bridge between Shelterin components [23–26]. TPP1 binds to TIN2 and POT1 that is essential for binding and calling telomerase to the ends of chromosomes [27,28]. finally, RAP1 align with TRF2 to binds the telomere and in addition, this factor binds to nontelomeric regions and plays a role in processes such as gene expression regulation [17,29,30] (Fig. 1).
4. Telomere length regulation Telomere length in humans is regulated by telomerase enzyme and the telomerase enzyme by attaching to the end of the guanine-rich area changed the telomere length [45]. during embryonic development, this enzyme has highly expressed, but its expression is suppressed in most somatic cells several weeks after birth, however, high levels of telomerase expression are observed in cells with high generative potentials, such as stem cells, lymphocytes, germ cells and cancer cells [46] (Fig. 3). The DNA polymerase-1 is a one-way enzyme that can’t replicate all of the bases at the 3' end of chromosome, consequently in each cycle of the replication process, one of the chromosome ends can't be fully synthesized and part of its structure disappears and if cells can't solve this replication problem, they are not able pass on their genetic content to the next generation [47,48] (Fig. 4). The telomere length regulation by the telomerase enzyme is a multistage process. In the first step, nucleotides present at the end of the 3' end DNA telomeres form a hybrid with the RNA transported by the telomerase enzyme. In the second step, the gap at the end of leading strand is filled and finally, the newly synthesized strand moves in the direction of 5', allowing the creation of a new gap and this cycle is repeated [25,47]. Telomere length regulation is done throughout the cell cycle and telomerase adds telomere sequences at S stage of the cell cycle [49] (Fig. 5).
3. Telomerase holoenzyme complex Telomerase enzyme is a specific DNA polymerase enzyme that adds new telomeric sequences to the chromosome ends [4,7,31–34]. This enzyme consists of two parts, the central part is TERT (Telomerase Reverse Transcriptase) protein and the accessory part is TERC (Telomerase RNA component) an RNA component that is transported by the central part and both of these parts provide a pattern for the synthesis of telomeric sequences [35–37]. Telomerase enzymes seem to be assembled in Cajal bodies, where the protein component (TERT) and its RNA component (TERC) get together to form the enzymatic ribonucleoprotein complex [38,39]. Another accessory component of this protein enzyme is Dyskerin, which forms a central complex with three other small proteins, NHP2, NOP10 and GAR1. Dyskerin is essential for the function of the telomerase [40,41]. Cajal body telomerase-1
5. Telomere length and cell senescence As Hayflick et al. [50] showed, the cells stopped their divisions after several passages and these process are referred to "Replicative Senescence". This condition causes a lot of alteration such as morphology, gene and protein expression changes in the cells [51]. There are several important factors to suppress proliferation of the cells, most notably, telomere length shortening, DNA damage and tumor suppressor signaling [52,53]. Although telomere shortening may not be the primary factor in acute cellular senescence but the reduction in telomere length and oxidative stress together can increase the probability of cell entering to the senescence condition [52]. Telomere length shortening in Fig. 1. Human telomere structure and telomerase recruitment. (a) linear chromosome that shows the position of telomere at the end of the chromosome (b) Telomeric DNA is bound by the sheltering complex consisting of six proteins: TRF1, TRF2, POT1, TIN2, TPP1 and RAP1. TRF1 and TRF2 bind to double-stranded telomeric DNA, TIN2 forms a bridge with TRF1 and TRF2 and TPP1. POT1 bind to singlestranded telomeric DNA. On the other hand, the figure shows telomerase recruitment to the chromosome end for telomere length regulation.
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Fig. 2. Schematic structure of the telomerase complex that assembly in Cajal bodies. The figure demonstrates Telomerase enzyme parts: hTERT, hTERC, Dyskerin, NOP10, NHP2, GAR1 and TCAB1 and relationship of telomerase with telomere shelterin complex at the end of the chromosome.
Fig. 3. Telomere length and proliferation capacity (a) X axis show proliferation age and Y axis show telomere length. Stem cells are telomerase positive and their telomere length is consonant and stable but most somatic cells are telomerase negative and some base pair is reducing in each cell division of their telomere. In pathological condition hTERT reactive in somatic cells and these cells become immortal with high proliferative capacity. (b) This figure shows the effect of cells differentiation on their telomere length that is reduced with differentiation.
tissue repair, so senescence of stem and progenitor cells is considered as an important factor in the aging process [58]. One of the basic characteristics of stem cells is the presence of telomerase enzyme activity and their stable remaining of telomere lengths [59,60]. Stem cells exist in different regions of the body and it has been shown that telomere length differs in stem cells at the different parts of the mice tissue and the longest telomere length is found in the skin, small intestine, cornea, testis, and brain tissue [61]. Although the telomere length seems to be stable in stem cells, despite the activity of the telomerase enzyme, evidence has shown that telomere shortening is also observed in these cells [62]. After the clonal expansion in cell injury or special conditions such as disease, the telomere length reduce and cause senescence in these cells and this hypothesis is supported based on data from bone marrow originated cells that have low migratory characteristics and severe telomere shortening in patients with coronary artery bypass graft [62]. The best-known characteristic is the hematopoietic stem cell, in
the process of replication and accumulation of DNA damage causes cell senescence in various tissues and on the other hand, short telomere length is considered as one of the main factors in the replicative senescence [54]. Approximately, the End Replication Problem causes the loss of nearly 100 base pairs of telomere nucleotide during each cell population proliferation [55]. Additionally, the status of the telomere length and the presence or absence of proteins involved in the formation of the Shelterin complex are very important for the induction of these senescence process [56]. Studies have shown that disturbance in telomere-binding proteins causes primary senescence in cells, such as when TRF2 inhibition in human primary fibroblasts induces senescence is due to protein-53 (P53) and retinoblastoma activity [57] (Fig. 6).
6. Telomere and telomerase status in stem cells Stem and progenitor cells play an important role in homeostasis and 11
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Fig. 4. This figure demonstrates End Replication Problem. DNA polymerase on leading strand produces the leading strand copy but DNA polymerase that binds to lagging strand can’t copy the lagging strand copy and makes separated segments that called Okazaki fragments.
continue the division and proliferation of cells to exit from this critical condition [44,67]. Most of the cancer cells in humans have a shorter telomere, while the level of telomerase expression is high [68]. The importance of the telomerase enzyme in the development of acute myeloid leukemia (AML) has been increased by showing the need for hTERT to growth and expansion of AML in a mouse model [69]. The progressive telomere length shortening is well described in the blood malignancies [70]. In addition, there is evidence that excessive telomere shortening may cause cancer cells to proliferate by increasing the expression of telomerase enzyme or activating this enzyme [71]. Increasing of hTERT expression can effectively increase cell proliferation and possibly lead to be a malignant phenotype [72].
that studies have reported that telomere length is lower in bone marrow than liver and cord blood cells [63] calling attention, studies confirm the age-related telomere shortening in hematopoietic stem cells [64].
7. Telomere and telomerase status in cancer Tumorigenesis is a major factor that greatly affects life expectancy and the short telomere length is a critical factor for cancer progression [65]. Progressive shortening of telomere length activates the immune response system against DNA damage [33]. According to studies on fibroblast cells, in the absence of telomerase enzyme, despite the increase in the number of cell division, the telomere length is reduced [66]. In normal somatic cells, the telomerase enzyme is suppressed and telomere length is reduced with each division until its structure is ending up and reaching a critical point, where it leads to the stopping of cell division [67]. In some cases, telomerase enzyme is re-activated to
Fig. 5. Telomere length regulation by telomerase is a multistage process. 1. Binding that this stage telomerase recruitment to the G overhang region and attach 2. Elongation is making of the new sequence by RNA template of telomerase 3. Translocation that telomerase separate and translocate and finally 4. Polymerization that new sequence attaches together.
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Fig. 6. The relationship between of telomere length and replicative senescence. With each cell division telomere becomes shorter until reaching the critical point that is controlled by P53 protein and Rb and finally cells become senescent.
8. Telomere and telomerase in blood cells
8.2. T and B lymphocytes
8.1. Hematopoietic stem cells (CD34+)
Telomere shortening in T and B lymphocyte has been observed with increasing in age and number of cell division in in vivo conditions [37,83]. Son et al. [84], in a cross-sectional study of CD4+ cells in 121 normal donors with age group ranging from infants to 94-year-old individuals showed that the telomere shortening in CD4+ and CD8+ lymphocytes were 35 and 26 bp/year, respectively [84]. Friedrich et al. [85] showed telomere length changes during human embryonic development in white blood cells and they observed rapid and significant shortening of the telomere restriction fragment between the weeks 27nd–32nd of gestation. While there was no evidence of this fragment shortening between pregnancy weeks 33–42 [85]. Rufer et al. [86] in a large cohort study (with a population of more than 500 donors with a 0–90-year age range), confirmed that the mean telomere length in naive CD4+ was larger than memory CD4+ [86]. Monteiro et al. (1996) showed that CD8+ CD28- T-cell lymphocytes have a shorter telomere length in compared with CD8+ CD28+ T lymphocytes [87]. The amount of telomere length shortening per cell division varies from 50 to 100 bp per/year in naive and memory T lymphocytes. It is interestingly to note that naive T lymphocytes have a longer telomere and higher T-cell division count than T lymphocytes [88]. The studies on long-term cultures of CD4+ and CD8+ T lymphocytes showed, when the telomerase levels are high, telomere length is also stable in these cells while as the telomerase level is decreased, the telomere length is also changed and becomes unstable [88]. Despite the many similarities between T and B lymphocytes, these cells have specific properties for telomere length regulation and telomerase enzyme [83]. Such T lymphocytes, telomere length is shortened in B lymphocytes with increasing in age, but this telomere shortening in B lymphocytes occur less rapidly than T lymphocytes (19 bp per year for B lymphocytes in comparison with 30–50 bp per year for T-lymphocytes) [84]. One of the major differences between B and T lymphocytes on the relative telomeres length is in the subset of these cells and unlike T lymphocytes, there is no significant difference in telomere length between memory and naive B lymphocytes, while the B lymphocytes in the germinal region of tonsils have longer telomeres than
Although telomerase enzyme activity is not observed in most somatic cells, but this enzyme activity is low in hematopoietic stem cells [73–75]. Against telomerase activity, the reduction in telomere length is observed both in white blood cells and in hematopoietic stem cells in in vitro conditions [76,77]. Telomerase enzyme activity has been detected in different origin of CD34+ cells and has been significantly increased after the expansion of these cells in in vitro condition [78]. Using the rapid and sensitive technique of TRAP (Telomeric Repeat Amplification Protocol) assay, it was observed that the proliferation of CD34+ cells developed in in vitro conditions and the activation of the cell cycle in response to cytokines significantly depends on increasing in the expression of the telomerase enzyme that is responsible for regulation of the telomere length. However, 1–2 kilobases of telomere length were reduced after four weeks of culture [79]. Vaziri et al. [80] showed that the hematopoietic stem cells isolated from the bone marrow had shorter telomeres than the same type of cells derived from the embryo liver or umbilical cord and this finding proves the shorting of the telomere length in the hematopoietic stem cell by increasing of age [63]. Low levels of telomerase enzyme activity can be detected in hematopoietic stem cells (HSCs) and in some cells derived from these cells, such as peripheral blood lymphocytes [81]. Changes in telomere length have been observed in cases such as myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML), in these cases the telomere is shortened, cells inactivated and ineffective hematopoiesis leads to progression of leukemia [82]. Telomerase activity increases in response to cytokines in hematopoietic stem cells and it is reduced in cells that differentiated from this cell line with increasing in age [73]. The temporary activation of telomerase in committed cells can prevent telomere length shortening and these findings indicate that one of the most important roles of telomerase enzyme in hematopoietic stem cells is avoiding of the reduction of telomere length shortening during fast cell divisions [76].
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their naive and memory B lymphocytes, so these findings confirm differences in telomere length regulation in B and T lymphocytes [88]. An example of telomerase regulation in in-vivo is seen in B lymphocytes. These cells located in the germinal region and express high levels of telomerase enzyme [89]. Hu et al. [90] reported that telomerase was not activated in the presence of a high proliferation of B-lymphocytestimulated cytokines. Therefore, this finding confirmed the independence of cell proliferation and activation of telomerase enzyme [90].
9.4. Interleukin-7 Interleukin-7 is secreted by bone marrow stromal cells and thymus, which develops T and B lymphocytes and the IL-7 signaling pathway is required to survive the T lymphocytes. In addition, it is important to differentiate and expansion of B lymphocytes [108]. Also this cytokine has a vital role in the homeostasis of CD8+ lymphocytes and has been observed that it is important for the proliferation of naive T lymphocytes in animal models [109]. 9.5. Interleukin-15
9. Effective key immune cytokines
This cytokine can bind to a wide range of cells, such as mononuclear cells and activated T lymphocytes. IL-15 also binds to the IL-2 receptor on activated T lymphocytes and participates in the signaling pathway. Against to IL-2, IL-15 is expressed in tissues such as placenta, skeletal muscle, kidneys and activated monocytes [110]. This cytokine plays an essential role in the activation and development of natural killer cells (NK), with the involvement of the IL-2 receptor [37,111].
Cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation [91]. Many effective cytokines have been identified in hematopoiesis and have been purified according to the type of colony that forms of hematopoietic progenitor cells [92,93]. The function and receptors of these cytokines have been confirmed on genetically modified mice. Also, many cytokines directly bind to their receptors on hematopoietic stem cells and regulate many aspects of these cellular functions, such as self-renewal, differentiation, and apoptosis [94]. a large number of different studies on hematopoietic stem cells have shown that these cells respond to a wide range of cytokines and on the other hand Study on cytokines involved in the development of hematopoietic stem cells promotes the development of cellular techniques and genetic therapies [37,94].
10. The role of cytokines on telomere length and telomerase In a study, Yu Li et al. [112] reported that IL-15 increases the expression of telomerase in CD8+ lymphocytes and high levels of hTERT expression cause to telomere length stability in these cells [112]. One of the notable points, in addition to IL-15 that activate the telomerase enzyme, is IL-7 not only the main cytokine for the development and hemostasis of T-lymphocytes but also activates this enzyme [113]. Similar to IL-15, IL-7 can’t completely stop telomere length shortening in T (CD8+) cells, since telomere length in T cells (CD4+) that treated with IL-7 were shortened on day 12 [113]. It is noteworthy that some cytokines, such as IFN-α and TGF-β can effectively affect the expression of telomerase enzyme [114,115]. Kawauchi et al. [116] observed in the study of natural killer cells that treated with IL-2, which it is essential for the proliferation of these cells, levels of telomerase enzyme were increasing 24 h after stimulation of these cells with IL-2 and this finding indicates that stimulation of cells with IL-2 activates hTERT and cause to cells have high telomere length [116]. In another experiment, Yang et al. [117] found that IL-7 induced low telomerase expression in CD4+ lymphocytes after 14 days’ culture and this increase of hTERT expression occurred after 7 days of culture [117]. In our previous study, we investigated the effects of IL-2, IL-7 and IL-15 cytokines on absolute telomere length and relative hTERT gene expression in umbilical cord blood mononuclear cells in a 21-day culture using Real-time PCR technique. The time points included days 0, 7, 14, and 21. The same study was conducted for cord blood hematopoietic stem cells (CD34+), with the exception that only days 0 and 21 were considered. Our findings of Real-time PCR showed that the hTERT gene expression was higher in the IL-2-treated group than the other experimental groups (IL-7 and IL-15) on the 7th day of culture. On the 14th day, the expression of this gene in the IL-15-treated group was more than two other groups and on the 21st day, the expression of hTERT in IL-2 and IL-15-treated groups was higher than of IL-7-treated group. These findings showed that IL-7 had a slight effect on the expression of the hTERT gene, IL-2 and IL-15, significantly affect the expression of this gene in umbilical cord mononuclear cells [118]. Also, Recent studies have shown that IL-2 significantly affects the hTERT gene expression in NK cells and increases the catalytic part activity of telomerase enzyme (hTERT) in such way that increases the hTERT gene expression and subsequent increment of telomerase enzyme activity occurs both in pre-translation and post-translation processes [56]. On the other hand, previous studies have shown that stimulation of natural killer cells in response to IL-2 is due to phosphorylation of JAK, STAT, Syk, CrKl and activation of RAS, PIK3, MAPK and some transcription factors such as AP-1 [119]. Studies by Kiyotaka Kawauchi et al. [116]
9.1. Stem cell factor Stem cell factor, also known as the "steel factor", is a cytokine that is secreted by a number of cells and it acts by binding to c-kit, a tyrosine kinase receptor expressed in all types of hematopoietic stem cells. With significant reduction of the c-kit expression, the proliferation and duplication of hematopoietic stem cells decreases [95]. Although the stem cell factor is not necessary for the production of hematopoietic stem cells, several studies have shown that this factor prevents of stem cell apoptosis [96]. The stem cell factor is present in almost combinations of different cytokines used to date and self-renewal ability of this factor in the hematopoietic stem cells of the fetus liver is more than of adult hematopoietic stem cells in in vitro and this feature requires the involvement of other factors [97]. The presence of NF-κB and cathepsin K decreases the stem cell factor and decreases in this factor alter the location of the hematopoietic stem cells [98]. 9.2. Flt3 FLT3 (Fms-like tyrosine kinase 3) is also known as (FLK-2), a fetal liver kinase-2 and is expressed in a wide range of human cells (the myelogenous lineage to B lymphocyte) [99]. In the healthy bone marrow, the expression of Flt3 is limited to primary precursors (CD34+), in which a high level of CD117 is expressed [100]. Also, flt3 is expressed in a wide range of hematological malignancies, such as chronic myeloid leukemia [101]. 9.3. Interleukin-2 Interleukin-2 was detected as a growth factor of T lymphocytes [37]. It was later found that this cytokine was involved in the growth and activation of B-lymphocytes, natural killer cells and monocytes [102]. Along with the function of this cytokine in in vitro conditions, studies have shown that IL-2 plays an important role in the development of T lymphocytes in in vivo conditions [103]. This cytokine plays an important role in the proliferation, survival and differentiation of T lymphocytes into memory cells [104–107]. 14
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signaling pathway that protein kinase C plays a key role in hTERT gene expression [126].
revealed that IL-2 activates ERK and AKT in the NK-92 cell line. Therefore, ERK and AKT are likely involved in activating the telomerase enzyme in response to IL-2 in the NK-92 cell line [56]. Our findings showed that hTERT expression was highest on day fourteen [118]. Wallace et al. [120] observed that these two cytokines cause to survive and proliferation of lymphocyte [117]. Similarly, Yu Li et al. [112] showed that the expression of the catalytic portion of the telomerase enzyme imported from out of the cell keeps the telomere in CD8+ and CD4+ cells and increases the cellular proliferation and IL-15 probably maintains the proliferative property of CD8+ cells [30,121]. Furthermore, the IL-15 activates the JAK /STATs and PI3K /AKT signaling pathways and probably these signaling pathways express the hTERT gene and activate telomerase enzyme activity [30]. Interestingly, in addition to IL-15, IL-7 can also activate the telomerase enzyme in T lymphocytes [113]. Yinhua Yang et al. [117], it was found that IL-7 caused hTERT gene expression in the T lymphocytes at very low level, however, it was also demonstrated that memory and naïve T lymphocytes exhibit a different response to IL-7 and hTERT gene is more expressed in naive T lymphocytes than memory T lymphocytes [117]. Since it was unveiled which telomerase enzyme activity is required to maintain the telomere length, it can be concluded that telomere length has a strong correlation with the activity of telomerase enzyme. However, in previous studies on IL-2-treated NK-92 cells, inhibition of telomerase using a specific inhibitor was not significantly correlated with telomere length shortening [116]. In reverse, in a study on K567 cells, telomerase enzyme inhibition significantly reduced the telomere length [122]. In the case of IL-7 and IL-15, our results showed that when these cytokines were used the absolute telomere length was increased from the 7th day to the 14th day of culture and was reduced from the 14th day to the 21st day. Also, this pattern was observed in the hTERT gene expression, which indicates a correlation between the absolute telomeres length and hTERT gene expression [118]. In a study, Wallace et al. [120] demonstrate that the maximum expansion of cells occurs on the 14th day of culture and cell expansion is much lower in the early and late days of the culture because when cells re-treated with both IL-7 and IL-15, they preserve their intact phenotypes by increasing the telomere length and telomerase enzyme expression. On the other hand, the increment of telomere length and hTERT gene expression is directly related to cell proliferation [120]. Blackburn et al. [123] reported that decreasing the telomerase enzyme activity in high proliferative cells decreases the telomere length in the cell population and cells death occur after excessive telomere shortening [123]. Many studies have shown that telomerase enzyme impairment in cultured cells reduces the telomere length in these cells [3,123,124]. Previous findings have proved that hTERT gene expression plays a key role in maintaining telomere length and protecting of telomere length which maintains the high proliferative property in the cells [125]. Recently, it has been proven that IL-7 protects and maintains naive T-cell lymphocytes in comparison to IL-15 stimulates the maturity of memory T lymphocytes [120]. In line with our results, it has been proved that IL-7 and IL-15 maintain naïve phenotype in cells that treated with these cytokines and with the lengthening of the telomere, hTERT gene expression was approximately increased [112]. When IL-7 was used the highest telomere length was obtained on the 14th day of culture, which was probably due to the delayed response of the cells to the cytokine. As previously mentioned in a study on T lymphocytes, it was observed that cells had shown a delayed expansion in response to IL-7 because this cytokine increases hTERT gene expression by activating JaK3 and PIK3/AKT signaling pathways and increasing this gene expression leads to an increase in the telomere length and finally with an increase in the absolute telomeres length, cells proliferate and expand exponentially [30]. IL-15 maintains telomere length in high levels on memory T lymphocytes that have been cultured for a long time by inducing overexpression of telomerase [30]. In general, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. Also, it is estimated with regard to the NF/kB
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Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha
Telomerase activity and telomere on stem progeny senescence a
b,e
c
T
d,e
Balal Brazvan , Abbas Ebrahimi-Kalan , Kobra Velaei , Ahmad Mehdipour , ⁎ Zeynab Aliyari serejf,i, Ayyub Ebrahimig, Mohammad Ghorbania, Omid Cheraghih, , j,⁎ Hojjatollah Nozad Charoudeh a
Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran c Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran d Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran e Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran f Applied Cell Sciences Department, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran g Department of Molecular Biology and Genetic, Faculty of Arts and Sciences, Halic Uuniversity, Istanbul, Turkey h Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran i Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran j Drug Applied research center, Tabriz University of Medical Sciences, Tabriz, Iran b
A R T I C LE I N FO
A B S T R A C T
Keywords: Telomere Telomerase Hematopoietic stem cells Cytokine
The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme. Human Telomerase Reverse Transcriptase (hTERT) gene expression plays an important role in maintaining telomere length and high proliferative property of cells. Except a low activity of telomerase enzyme in hematopoietic and few types of stem cells, most of somatic cells didn’t showed telomerase activity. Moreover, cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation. Also, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. In this review we have tried to talk about effects of immune cell cytokines on telomerase expression/telomere length and the induction of telomerase expression by cytokines.
1. History of telomere study The telomere was described, for the first time, as a protective structure at the end of the chromosomes in 1930 by Hermann J. Muller and Barbara McClintock to prevent the end-to-end fusion that may occur in the chromosomes and lead to cell death [1]. In 1960, Hayflick described a biological view of aging. He concluded that human diploid cells indicating a limitation in proliferation and Hayflick’s limit is considered to be the maximum number of cell divisions [2,3]. In 1970, James D. Watson defined the End Replication Problem during DNA replication. Indeed DNA polymerase couldn’t completely replicate the end of the 5' chromosome [4]. Then, in 1973, Olovnikov linked the cell senescence with the end replication problem in the "Theory of Marginotomy". In this theory, telomere shortening was considered as an
⁎
internal hourly mechanism of aging. later in 1980 this theory had approved and they observed the shortening of telomere length during in vitro cell proliferation conditions [5]. Elizabeth Blackburn found that the molecular structure of Tetrahymena pyriformis telomeres has a rich of guanine (G) and thymine (T) nucleotide [6] and in 1984 Elizabeth Blackburn et al. isolated an enzyme that called telomerase. They proved, this enzyme is responsible for telomere length regulation and later reported that the presence of telomerase activity in human cancer cells have led to the immortality of these cells [7]. This is true that telomerase enzyme is not alone in telomere length regulation and another mechanism such as alternative telomere length has an important [8] and telomere and telomerase have been studied extensively because of its important role in physiologic aging, cancer pathology and premature aging syndrome.
Corresponding authors. E-mail addresses: [email protected] (O. Cheraghi), [email protected] (H. Nozad Charoudeh).
https://doi.org/10.1016/j.biopha.2018.02.073 Received 31 December 2017; Received in revised form 3 February 2018; Accepted 19 February 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.
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2. Telomere structure
(TCAB1) is another protein that binds to the enzyme and adjusts its transit [42]. In vertebrates, the RNA that transmitted by telomerase enzyme has about 382–559 nucleotides [43]. The number of RNA nucleotides transmitted by the human telomerase enzyme is about 451 nucleotides and its nucleotide sequence composed of 5'-CUAACCCU AAC-3' sequences, which is responsible for coding the telomere sequences [44] (Fig. 2).
The ends of linear chromosomes have been formed with a special heterochromatin structure that called telomere and this structure protect the end of the chromosome from degradation and act as DNA repair mechanism, therefore, the telomere is a structure that is essential for the stability of the chromosome [9,10]. The mammalian telomeres consist of several kilobases, for example, telomere length in humans is 10–15 kb and 25–50 kb in mice that consisting of repetitive TTAGGG sequences [1,11,12]. This specific rich region of guanine structure is characterized by the presence of 30–400 nucleotides at the end of the 3′ chromosome [13,14]. Telomeres are linked to specific structures that called Shelterin, which is essential for telomere length regulation, telomere protection from the DNA damage response system and keep the chromosome end of the DNA repair machine [15]. The Shelterin Complex consists of six central proteins; TRF1 (telomeric repeat binding factor 1), TRF2 (telomeric repeat binding factor 2), TIN2 (TRF1-interacting protein 2), POT1 (protection of telomeres protein 1), TPP1 (TIN2- and POT1-interacting protein) and RAP1 (repressor/activator protein 1) [16–19]. Homodimers of TRF1 and TRF2 bind to doublestrand telomeric DNA in one side and TIN2 on the other side which form Shelterin core complex [20]. Other proteins such POT1 binds to single strand telomeric DNA sequence [21,22]. TIN2 binds to TRF1 and TRF2 and acts as a bridge between Shelterin components [23–26]. TPP1 binds to TIN2 and POT1 that is essential for binding and calling telomerase to the ends of chromosomes [27,28]. finally, RAP1 align with TRF2 to binds the telomere and in addition, this factor binds to nontelomeric regions and plays a role in processes such as gene expression regulation [17,29,30] (Fig. 1).
4. Telomere length regulation Telomere length in humans is regulated by telomerase enzyme and the telomerase enzyme by attaching to the end of the guanine-rich area changed the telomere length [45]. during embryonic development, this enzyme has highly expressed, but its expression is suppressed in most somatic cells several weeks after birth, however, high levels of telomerase expression are observed in cells with high generative potentials, such as stem cells, lymphocytes, germ cells and cancer cells [46] (Fig. 3). The DNA polymerase-1 is a one-way enzyme that can’t replicate all of the bases at the 3' end of chromosome, consequently in each cycle of the replication process, one of the chromosome ends can't be fully synthesized and part of its structure disappears and if cells can't solve this replication problem, they are not able pass on their genetic content to the next generation [47,48] (Fig. 4). The telomere length regulation by the telomerase enzyme is a multistage process. In the first step, nucleotides present at the end of the 3' end DNA telomeres form a hybrid with the RNA transported by the telomerase enzyme. In the second step, the gap at the end of leading strand is filled and finally, the newly synthesized strand moves in the direction of 5', allowing the creation of a new gap and this cycle is repeated [25,47]. Telomere length regulation is done throughout the cell cycle and telomerase adds telomere sequences at S stage of the cell cycle [49] (Fig. 5).
3. Telomerase holoenzyme complex Telomerase enzyme is a specific DNA polymerase enzyme that adds new telomeric sequences to the chromosome ends [4,7,31–34]. This enzyme consists of two parts, the central part is TERT (Telomerase Reverse Transcriptase) protein and the accessory part is TERC (Telomerase RNA component) an RNA component that is transported by the central part and both of these parts provide a pattern for the synthesis of telomeric sequences [35–37]. Telomerase enzymes seem to be assembled in Cajal bodies, where the protein component (TERT) and its RNA component (TERC) get together to form the enzymatic ribonucleoprotein complex [38,39]. Another accessory component of this protein enzyme is Dyskerin, which forms a central complex with three other small proteins, NHP2, NOP10 and GAR1. Dyskerin is essential for the function of the telomerase [40,41]. Cajal body telomerase-1
5. Telomere length and cell senescence As Hayflick et al. [50] showed, the cells stopped their divisions after several passages and these process are referred to "Replicative Senescence". This condition causes a lot of alteration such as morphology, gene and protein expression changes in the cells [51]. There are several important factors to suppress proliferation of the cells, most notably, telomere length shortening, DNA damage and tumor suppressor signaling [52,53]. Although telomere shortening may not be the primary factor in acute cellular senescence but the reduction in telomere length and oxidative stress together can increase the probability of cell entering to the senescence condition [52]. Telomere length shortening in Fig. 1. Human telomere structure and telomerase recruitment. (a) linear chromosome that shows the position of telomere at the end of the chromosome (b) Telomeric DNA is bound by the sheltering complex consisting of six proteins: TRF1, TRF2, POT1, TIN2, TPP1 and RAP1. TRF1 and TRF2 bind to double-stranded telomeric DNA, TIN2 forms a bridge with TRF1 and TRF2 and TPP1. POT1 bind to singlestranded telomeric DNA. On the other hand, the figure shows telomerase recruitment to the chromosome end for telomere length regulation.
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Fig. 2. Schematic structure of the telomerase complex that assembly in Cajal bodies. The figure demonstrates Telomerase enzyme parts: hTERT, hTERC, Dyskerin, NOP10, NHP2, GAR1 and TCAB1 and relationship of telomerase with telomere shelterin complex at the end of the chromosome.
Fig. 3. Telomere length and proliferation capacity (a) X axis show proliferation age and Y axis show telomere length. Stem cells are telomerase positive and their telomere length is consonant and stable but most somatic cells are telomerase negative and some base pair is reducing in each cell division of their telomere. In pathological condition hTERT reactive in somatic cells and these cells become immortal with high proliferative capacity. (b) This figure shows the effect of cells differentiation on their telomere length that is reduced with differentiation.
tissue repair, so senescence of stem and progenitor cells is considered as an important factor in the aging process [58]. One of the basic characteristics of stem cells is the presence of telomerase enzyme activity and their stable remaining of telomere lengths [59,60]. Stem cells exist in different regions of the body and it has been shown that telomere length differs in stem cells at the different parts of the mice tissue and the longest telomere length is found in the skin, small intestine, cornea, testis, and brain tissue [61]. Although the telomere length seems to be stable in stem cells, despite the activity of the telomerase enzyme, evidence has shown that telomere shortening is also observed in these cells [62]. After the clonal expansion in cell injury or special conditions such as disease, the telomere length reduce and cause senescence in these cells and this hypothesis is supported based on data from bone marrow originated cells that have low migratory characteristics and severe telomere shortening in patients with coronary artery bypass graft [62]. The best-known characteristic is the hematopoietic stem cell, in
the process of replication and accumulation of DNA damage causes cell senescence in various tissues and on the other hand, short telomere length is considered as one of the main factors in the replicative senescence [54]. Approximately, the End Replication Problem causes the loss of nearly 100 base pairs of telomere nucleotide during each cell population proliferation [55]. Additionally, the status of the telomere length and the presence or absence of proteins involved in the formation of the Shelterin complex are very important for the induction of these senescence process [56]. Studies have shown that disturbance in telomere-binding proteins causes primary senescence in cells, such as when TRF2 inhibition in human primary fibroblasts induces senescence is due to protein-53 (P53) and retinoblastoma activity [57] (Fig. 6).
6. Telomere and telomerase status in stem cells Stem and progenitor cells play an important role in homeostasis and 11
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Fig. 4. This figure demonstrates End Replication Problem. DNA polymerase on leading strand produces the leading strand copy but DNA polymerase that binds to lagging strand can’t copy the lagging strand copy and makes separated segments that called Okazaki fragments.
continue the division and proliferation of cells to exit from this critical condition [44,67]. Most of the cancer cells in humans have a shorter telomere, while the level of telomerase expression is high [68]. The importance of the telomerase enzyme in the development of acute myeloid leukemia (AML) has been increased by showing the need for hTERT to growth and expansion of AML in a mouse model [69]. The progressive telomere length shortening is well described in the blood malignancies [70]. In addition, there is evidence that excessive telomere shortening may cause cancer cells to proliferate by increasing the expression of telomerase enzyme or activating this enzyme [71]. Increasing of hTERT expression can effectively increase cell proliferation and possibly lead to be a malignant phenotype [72].
that studies have reported that telomere length is lower in bone marrow than liver and cord blood cells [63] calling attention, studies confirm the age-related telomere shortening in hematopoietic stem cells [64].
7. Telomere and telomerase status in cancer Tumorigenesis is a major factor that greatly affects life expectancy and the short telomere length is a critical factor for cancer progression [65]. Progressive shortening of telomere length activates the immune response system against DNA damage [33]. According to studies on fibroblast cells, in the absence of telomerase enzyme, despite the increase in the number of cell division, the telomere length is reduced [66]. In normal somatic cells, the telomerase enzyme is suppressed and telomere length is reduced with each division until its structure is ending up and reaching a critical point, where it leads to the stopping of cell division [67]. In some cases, telomerase enzyme is re-activated to
Fig. 5. Telomere length regulation by telomerase is a multistage process. 1. Binding that this stage telomerase recruitment to the G overhang region and attach 2. Elongation is making of the new sequence by RNA template of telomerase 3. Translocation that telomerase separate and translocate and finally 4. Polymerization that new sequence attaches together.
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Fig. 6. The relationship between of telomere length and replicative senescence. With each cell division telomere becomes shorter until reaching the critical point that is controlled by P53 protein and Rb and finally cells become senescent.
8. Telomere and telomerase in blood cells
8.2. T and B lymphocytes
8.1. Hematopoietic stem cells (CD34+)
Telomere shortening in T and B lymphocyte has been observed with increasing in age and number of cell division in in vivo conditions [37,83]. Son et al. [84], in a cross-sectional study of CD4+ cells in 121 normal donors with age group ranging from infants to 94-year-old individuals showed that the telomere shortening in CD4+ and CD8+ lymphocytes were 35 and 26 bp/year, respectively [84]. Friedrich et al. [85] showed telomere length changes during human embryonic development in white blood cells and they observed rapid and significant shortening of the telomere restriction fragment between the weeks 27nd–32nd of gestation. While there was no evidence of this fragment shortening between pregnancy weeks 33–42 [85]. Rufer et al. [86] in a large cohort study (with a population of more than 500 donors with a 0–90-year age range), confirmed that the mean telomere length in naive CD4+ was larger than memory CD4+ [86]. Monteiro et al. (1996) showed that CD8+ CD28- T-cell lymphocytes have a shorter telomere length in compared with CD8+ CD28+ T lymphocytes [87]. The amount of telomere length shortening per cell division varies from 50 to 100 bp per/year in naive and memory T lymphocytes. It is interestingly to note that naive T lymphocytes have a longer telomere and higher T-cell division count than T lymphocytes [88]. The studies on long-term cultures of CD4+ and CD8+ T lymphocytes showed, when the telomerase levels are high, telomere length is also stable in these cells while as the telomerase level is decreased, the telomere length is also changed and becomes unstable [88]. Despite the many similarities between T and B lymphocytes, these cells have specific properties for telomere length regulation and telomerase enzyme [83]. Such T lymphocytes, telomere length is shortened in B lymphocytes with increasing in age, but this telomere shortening in B lymphocytes occur less rapidly than T lymphocytes (19 bp per year for B lymphocytes in comparison with 30–50 bp per year for T-lymphocytes) [84]. One of the major differences between B and T lymphocytes on the relative telomeres length is in the subset of these cells and unlike T lymphocytes, there is no significant difference in telomere length between memory and naive B lymphocytes, while the B lymphocytes in the germinal region of tonsils have longer telomeres than
Although telomerase enzyme activity is not observed in most somatic cells, but this enzyme activity is low in hematopoietic stem cells [73–75]. Against telomerase activity, the reduction in telomere length is observed both in white blood cells and in hematopoietic stem cells in in vitro conditions [76,77]. Telomerase enzyme activity has been detected in different origin of CD34+ cells and has been significantly increased after the expansion of these cells in in vitro condition [78]. Using the rapid and sensitive technique of TRAP (Telomeric Repeat Amplification Protocol) assay, it was observed that the proliferation of CD34+ cells developed in in vitro conditions and the activation of the cell cycle in response to cytokines significantly depends on increasing in the expression of the telomerase enzyme that is responsible for regulation of the telomere length. However, 1–2 kilobases of telomere length were reduced after four weeks of culture [79]. Vaziri et al. [80] showed that the hematopoietic stem cells isolated from the bone marrow had shorter telomeres than the same type of cells derived from the embryo liver or umbilical cord and this finding proves the shorting of the telomere length in the hematopoietic stem cell by increasing of age [63]. Low levels of telomerase enzyme activity can be detected in hematopoietic stem cells (HSCs) and in some cells derived from these cells, such as peripheral blood lymphocytes [81]. Changes in telomere length have been observed in cases such as myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML), in these cases the telomere is shortened, cells inactivated and ineffective hematopoiesis leads to progression of leukemia [82]. Telomerase activity increases in response to cytokines in hematopoietic stem cells and it is reduced in cells that differentiated from this cell line with increasing in age [73]. The temporary activation of telomerase in committed cells can prevent telomere length shortening and these findings indicate that one of the most important roles of telomerase enzyme in hematopoietic stem cells is avoiding of the reduction of telomere length shortening during fast cell divisions [76].
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their naive and memory B lymphocytes, so these findings confirm differences in telomere length regulation in B and T lymphocytes [88]. An example of telomerase regulation in in-vivo is seen in B lymphocytes. These cells located in the germinal region and express high levels of telomerase enzyme [89]. Hu et al. [90] reported that telomerase was not activated in the presence of a high proliferation of B-lymphocytestimulated cytokines. Therefore, this finding confirmed the independence of cell proliferation and activation of telomerase enzyme [90].
9.4. Interleukin-7 Interleukin-7 is secreted by bone marrow stromal cells and thymus, which develops T and B lymphocytes and the IL-7 signaling pathway is required to survive the T lymphocytes. In addition, it is important to differentiate and expansion of B lymphocytes [108]. Also this cytokine has a vital role in the homeostasis of CD8+ lymphocytes and has been observed that it is important for the proliferation of naive T lymphocytes in animal models [109]. 9.5. Interleukin-15
9. Effective key immune cytokines
This cytokine can bind to a wide range of cells, such as mononuclear cells and activated T lymphocytes. IL-15 also binds to the IL-2 receptor on activated T lymphocytes and participates in the signaling pathway. Against to IL-2, IL-15 is expressed in tissues such as placenta, skeletal muscle, kidneys and activated monocytes [110]. This cytokine plays an essential role in the activation and development of natural killer cells (NK), with the involvement of the IL-2 receptor [37,111].
Cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation [91]. Many effective cytokines have been identified in hematopoiesis and have been purified according to the type of colony that forms of hematopoietic progenitor cells [92,93]. The function and receptors of these cytokines have been confirmed on genetically modified mice. Also, many cytokines directly bind to their receptors on hematopoietic stem cells and regulate many aspects of these cellular functions, such as self-renewal, differentiation, and apoptosis [94]. a large number of different studies on hematopoietic stem cells have shown that these cells respond to a wide range of cytokines and on the other hand Study on cytokines involved in the development of hematopoietic stem cells promotes the development of cellular techniques and genetic therapies [37,94].
10. The role of cytokines on telomere length and telomerase In a study, Yu Li et al. [112] reported that IL-15 increases the expression of telomerase in CD8+ lymphocytes and high levels of hTERT expression cause to telomere length stability in these cells [112]. One of the notable points, in addition to IL-15 that activate the telomerase enzyme, is IL-7 not only the main cytokine for the development and hemostasis of T-lymphocytes but also activates this enzyme [113]. Similar to IL-15, IL-7 can’t completely stop telomere length shortening in T (CD8+) cells, since telomere length in T cells (CD4+) that treated with IL-7 were shortened on day 12 [113]. It is noteworthy that some cytokines, such as IFN-α and TGF-β can effectively affect the expression of telomerase enzyme [114,115]. Kawauchi et al. [116] observed in the study of natural killer cells that treated with IL-2, which it is essential for the proliferation of these cells, levels of telomerase enzyme were increasing 24 h after stimulation of these cells with IL-2 and this finding indicates that stimulation of cells with IL-2 activates hTERT and cause to cells have high telomere length [116]. In another experiment, Yang et al. [117] found that IL-7 induced low telomerase expression in CD4+ lymphocytes after 14 days’ culture and this increase of hTERT expression occurred after 7 days of culture [117]. In our previous study, we investigated the effects of IL-2, IL-7 and IL-15 cytokines on absolute telomere length and relative hTERT gene expression in umbilical cord blood mononuclear cells in a 21-day culture using Real-time PCR technique. The time points included days 0, 7, 14, and 21. The same study was conducted for cord blood hematopoietic stem cells (CD34+), with the exception that only days 0 and 21 were considered. Our findings of Real-time PCR showed that the hTERT gene expression was higher in the IL-2-treated group than the other experimental groups (IL-7 and IL-15) on the 7th day of culture. On the 14th day, the expression of this gene in the IL-15-treated group was more than two other groups and on the 21st day, the expression of hTERT in IL-2 and IL-15-treated groups was higher than of IL-7-treated group. These findings showed that IL-7 had a slight effect on the expression of the hTERT gene, IL-2 and IL-15, significantly affect the expression of this gene in umbilical cord mononuclear cells [118]. Also, Recent studies have shown that IL-2 significantly affects the hTERT gene expression in NK cells and increases the catalytic part activity of telomerase enzyme (hTERT) in such way that increases the hTERT gene expression and subsequent increment of telomerase enzyme activity occurs both in pre-translation and post-translation processes [56]. On the other hand, previous studies have shown that stimulation of natural killer cells in response to IL-2 is due to phosphorylation of JAK, STAT, Syk, CrKl and activation of RAS, PIK3, MAPK and some transcription factors such as AP-1 [119]. Studies by Kiyotaka Kawauchi et al. [116]
9.1. Stem cell factor Stem cell factor, also known as the "steel factor", is a cytokine that is secreted by a number of cells and it acts by binding to c-kit, a tyrosine kinase receptor expressed in all types of hematopoietic stem cells. With significant reduction of the c-kit expression, the proliferation and duplication of hematopoietic stem cells decreases [95]. Although the stem cell factor is not necessary for the production of hematopoietic stem cells, several studies have shown that this factor prevents of stem cell apoptosis [96]. The stem cell factor is present in almost combinations of different cytokines used to date and self-renewal ability of this factor in the hematopoietic stem cells of the fetus liver is more than of adult hematopoietic stem cells in in vitro and this feature requires the involvement of other factors [97]. The presence of NF-κB and cathepsin K decreases the stem cell factor and decreases in this factor alter the location of the hematopoietic stem cells [98]. 9.2. Flt3 FLT3 (Fms-like tyrosine kinase 3) is also known as (FLK-2), a fetal liver kinase-2 and is expressed in a wide range of human cells (the myelogenous lineage to B lymphocyte) [99]. In the healthy bone marrow, the expression of Flt3 is limited to primary precursors (CD34+), in which a high level of CD117 is expressed [100]. Also, flt3 is expressed in a wide range of hematological malignancies, such as chronic myeloid leukemia [101]. 9.3. Interleukin-2 Interleukin-2 was detected as a growth factor of T lymphocytes [37]. It was later found that this cytokine was involved in the growth and activation of B-lymphocytes, natural killer cells and monocytes [102]. Along with the function of this cytokine in in vitro conditions, studies have shown that IL-2 plays an important role in the development of T lymphocytes in in vivo conditions [103]. This cytokine plays an important role in the proliferation, survival and differentiation of T lymphocytes into memory cells [104–107]. 14
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signaling pathway that protein kinase C plays a key role in hTERT gene expression [126].
revealed that IL-2 activates ERK and AKT in the NK-92 cell line. Therefore, ERK and AKT are likely involved in activating the telomerase enzyme in response to IL-2 in the NK-92 cell line [56]. Our findings showed that hTERT expression was highest on day fourteen [118]. Wallace et al. [120] observed that these two cytokines cause to survive and proliferation of lymphocyte [117]. Similarly, Yu Li et al. [112] showed that the expression of the catalytic portion of the telomerase enzyme imported from out of the cell keeps the telomere in CD8+ and CD4+ cells and increases the cellular proliferation and IL-15 probably maintains the proliferative property of CD8+ cells [30,121]. Furthermore, the IL-15 activates the JAK /STATs and PI3K /AKT signaling pathways and probably these signaling pathways express the hTERT gene and activate telomerase enzyme activity [30]. Interestingly, in addition to IL-15, IL-7 can also activate the telomerase enzyme in T lymphocytes [113]. Yinhua Yang et al. [117], it was found that IL-7 caused hTERT gene expression in the T lymphocytes at very low level, however, it was also demonstrated that memory and naïve T lymphocytes exhibit a different response to IL-7 and hTERT gene is more expressed in naive T lymphocytes than memory T lymphocytes [117]. Since it was unveiled which telomerase enzyme activity is required to maintain the telomere length, it can be concluded that telomere length has a strong correlation with the activity of telomerase enzyme. However, in previous studies on IL-2-treated NK-92 cells, inhibition of telomerase using a specific inhibitor was not significantly correlated with telomere length shortening [116]. In reverse, in a study on K567 cells, telomerase enzyme inhibition significantly reduced the telomere length [122]. In the case of IL-7 and IL-15, our results showed that when these cytokines were used the absolute telomere length was increased from the 7th day to the 14th day of culture and was reduced from the 14th day to the 21st day. Also, this pattern was observed in the hTERT gene expression, which indicates a correlation between the absolute telomeres length and hTERT gene expression [118]. In a study, Wallace et al. [120] demonstrate that the maximum expansion of cells occurs on the 14th day of culture and cell expansion is much lower in the early and late days of the culture because when cells re-treated with both IL-7 and IL-15, they preserve their intact phenotypes by increasing the telomere length and telomerase enzyme expression. On the other hand, the increment of telomere length and hTERT gene expression is directly related to cell proliferation [120]. Blackburn et al. [123] reported that decreasing the telomerase enzyme activity in high proliferative cells decreases the telomere length in the cell population and cells death occur after excessive telomere shortening [123]. Many studies have shown that telomerase enzyme impairment in cultured cells reduces the telomere length in these cells [3,123,124]. Previous findings have proved that hTERT gene expression plays a key role in maintaining telomere length and protecting of telomere length which maintains the high proliferative property in the cells [125]. Recently, it has been proven that IL-7 protects and maintains naive T-cell lymphocytes in comparison to IL-15 stimulates the maturity of memory T lymphocytes [120]. In line with our results, it has been proved that IL-7 and IL-15 maintain naïve phenotype in cells that treated with these cytokines and with the lengthening of the telomere, hTERT gene expression was approximately increased [112]. When IL-7 was used the highest telomere length was obtained on the 14th day of culture, which was probably due to the delayed response of the cells to the cytokine. As previously mentioned in a study on T lymphocytes, it was observed that cells had shown a delayed expansion in response to IL-7 because this cytokine increases hTERT gene expression by activating JaK3 and PIK3/AKT signaling pathways and increasing this gene expression leads to an increase in the telomere length and finally with an increase in the absolute telomeres length, cells proliferate and expand exponentially [30]. IL-15 maintains telomere length in high levels on memory T lymphocytes that have been cultured for a long time by inducing overexpression of telomerase [30]. In general, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. Also, it is estimated with regard to the NF/kB
11. Conclusion In conclusion, telomere length is reduced with each division of cells. Telomerase added the new nucleotide to telomeric DNA and there is one significant correlation between of telomere length and telomerase expression in all type of cells. Cytokines can affect telomerase expression and telomere length. It seems the induction of telomerase expression by immune cell cytokines is controlled through the PI3K/AKT and NF/kB signaling pathways hypothetically. Conflicts of interest All author declared no conflict of interest. References [1] María A. Blasco, Mammalian telomeres and telomerase: why they matter for cancer and aging, Eur. J. Cell Biol. 82 (9) (2003) 441–446. [2] Roger R. Reddel, The role of senescence and immortalization in carcinogenesis, Carcinogenesis 21 (3) (2000) 477–484. [3] Jerry W. Shay, Woodring E. Wright, Hayflick, his limit, and cellular ageing, Nat. Rev. Mol. Cell Biol. 1 (1) (2000) 72–76. [4] Carol Greider, Elizabeth Blackburn, Telomeres, Telomerase Et Cancer-La Telomerase Est Une Enzyme Qui Agit Sur Les Extremites Des Chromosomes. Detectee Dans De Nombreux Cancers Humains, Elle Serait Une Cible Nouvelle Pour Les, Pour la Science 222 (1996) 72–77. [5] Alexeij M. Olovnikov, A theory of marginotomy: the incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon, J. Theor. Biol. 41 (1) (1973) 181–190. [6] Lin Kah Wai, Telomeres, telomerase, and tumorigenesis–a review, Medscape Gen. Med. 6 (2004) 3. [7] Carol W. Greider, Elizabeth H. Blackburn, Identification of a specific telomere terminal transferase activity in tetrahymena extracts, Cell 43 (2) (1985) 405–413. [8] Anthony J. Cesare, Roger R. Reddel, Alternative Lengthening of Telomeres in Mammalian Cells, (2013). [9] Hiroyuki Takai, Agata Smogorzewska, Titia de Lange, DNA damage foci at dysfunctional telomeres, Curr. Biol. 13 (17) (2003) 1549–1556. [10] Maria A. Blasco, Telomere length, stem cells and aging, Nat. Chem. Biol. 3 (10) (2007) 640–649. [11] María A. Blasco, Telomeres and human disease: ageing, cancer and beyond, Nat. Rev. Genet. 6 (8) (2005) 611. [12] María A. Blasco, The epigenetic regulation of mammalian telomeres, Nat. Rev. Genet. 8 (4) (2007) 299. [13] Vladimir L. Makarov, Yoko Hirose, John P. Langmore, Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening, Cell 88 (5) (1997) 657–666. [14] Weihang Chai, et al., Human telomeres have different overhang sizes at leading versus lagging strands, Mol. Cell 21 (3) (2006) 427–435. [15] Wilhelm Palm, Titia de Lange, How shelterin protects mammalian telomeres, Annu. Rev. Genet. 42 (2008) 301–334. [16] T.itia De Lange, Shelterin: the protein complex that shapes and safeguards human telomeres, Gene Dev. 19 (18) (2005) 2100–2110. [17] Paula Martínez, et al., Rap1 protects from obesity through its extratelomeric role regulating gene expression, Cell Rep. 3 (6) (2013) 2059–2074. [18] Paula Martínez, María A. Blasco, Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins, Nat. Rev. Cancer 11 (3) (2011) 161. [19] Paula Martínez, Maria A. Blasco, Role of shelterin in cancer and aging, Aging Cell 9 (5) (2010) 653–666. [20] Jiunn-Liang Chen, Maria A. Blasco, Carol W. Greider, Secondary structure of vertebrate telomerase Rna, Cell 100 (5) (2000) 503–514. [21] Ming Lei, Elaine R. Podell, Thomas R. Cech, Structure of human Pot1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection, Nat. Struct. Mol. Biol. 11 (12) (2004) 1223. [22] Diego Loayza, Titia de Lange, Pot1 as a terminal transducer of Trf1 telomere length control, Nature 423 (6943) (2003) 1013. [23] David Frescas, Titia de Lange, Trf2-tethered Tin2 can mediate telomere protection by Tpp1/Pot1, Mol. Cell. Biol. 34 (7) (2014) 1349–1362. [24] Nam W. Kim, et al., Specific association of human telomerase activity with immortal cells and cancer, Science (1994) 2011–2015. [25] Jayakrishnan Nandakumar, Thomas R. Cech, Finding the end: recruitment of telomerase to the telomere, Nat. Rev. Mol. Cell Biol. 14 (2) (2013) 69. [26] Takai, K. Kaori, et al., Telomere protection by Tpp1/Pot1 requires tethering to Tin2, Mol. Cell 44 (4) (2011) 647–659. [27] Eladio Abreu, et al., Tin2-tethered Tpp1 recruits human telomerase to telomeres in vivo, Mol. Cell. Biol. 30 (12) (2010) 2971–2982. [28] Agueda M. Tejera, et al., Tpp1 is required for tert recruitment, telomere elongation during nuclear reprogramming, and normal skin development in mice, Dev. Cell
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