PubMed İndeksli Yayınlar Koleksiyonu / PubMed Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7645
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Review Citation - WoS: 9Citation - Scopus: 7Micrornas and Long Non-Coding Rnas as Novel Targets in Anti-Cancer Drug Development(Bentham Science Publishers, 2023) Çetinkaya, Melisa; Baran, Yusuf; Baran, Yusuf; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyNon-coding RNAs comprise the majority of RNAs that have been transcribed from the human genome, and these non-coding RNAs have essential regulatory roles in the cellular processes. They have been discovered to influence the expression of the genes, including tumor-suppressive and oncogenes, that establish the non-coding RNAs as novel targets for anti-cancer drug development. Among non-coding RNAs, microRNAs have been extensively studied in terms of cancer biology, and some microRNA-based therapeutics have been reached in clinical studies. Even though most of the research regarding targeting non-coding RNAs for anti-cancer drug development focused on microRNAs, long non-coding RNAs have also started to gain importance as potential therapeutic targets for cancer therapy. In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long non-coding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described.Article Citation - WoS: 11Citation - Scopus: 14MicroRNA-155 plays selective cell-intrinsic roles in brain-infiltrating immune cell populations during neuroinflammation(American Association of Immunologists, 2023) Thompson, J.W.; Ekiz, Hüseyin Atakan; Hu, R.; Huffaker, T.B.; Ramstead, A.G.; Ekiz, Hüseyin Atakan; Bauer, K.M.; Tang, W.W.; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyThe proinflammatory microRNA-155 (miR-155) is highly expressed in the serum and CNS lesions of patients with multiple sclerosis (MS). Global knockout (KO) of miR-155 in mice confers resistance to a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), by reducing the encephalogenic potential of CNS-infiltrating Th17 T cells. However, cell-intrinsic roles for miR-155 during EAE have not been formally determined. In this study, we use single-cell RNA sequencing and cell-specific conditional miR-155 KOs to determine the importance of miR-155 expression in distinct immune cell populations. Time-course single-cell sequencing revealed reductions in T cells, macrophages, and dendritic cells (DCs) in global miR-155 KO mice compared with wild-type controls at day 21 after EAE induction. Deletion of miR-155 in T cells, driven by CD4 Cre, significantly reduced disease severity similar to global miR-155 KOs. CD11c Cre-mediated deletion of miR-155 in DCs also resulted in a modest yet significant reduction in the development of EAE, with both T cell- and DC-specific KOs showing a reduction in Th17 T cell infiltration into the CNS. Although miR-155 is highly expressed in infiltrating macrophages during EAE, deletion of miR-155 using LysM Cre did not impact disease severity. Taken together, these data show that although miR-155 is highly expressed in most infiltrating immune cells, miR-155 has distinct roles and requirements depending on the cell type, and we have demonstrated this using the gold standard conditional KO approach. This provides insights into which functionally relevant cell types should be targeted by the next generation of miRNA therapeutics. Copyright © 2023 by The American Association of Immunologists, Inc.Article Citation - WoS: 22Citation - Scopus: 23A Single-Amino Acid Substitution in the Adaptor Lat Accelerates Tcr Proofreading Kinetics and Alters T-Cell Selection, Maintenance and Function(Nature Portfolio, 2023) Lo, Wan-Lin; Ekiz, Hüseyin Atakan; Kuhlmann, Miriam; Rizzuto, Gabrielle; Ekiz, H. Atakan; Kolawole, Elizabeth M.; Revelo, Monica P.; Andargachew, Rakieb; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LAT(G135D)) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LAT(G135D) T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LAT(G135D) T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LAT(G135D) show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity. Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.Book Part Citation - Scopus: 5Epitranscriptomics Changes the Play: M6a Rna Modifications in Apoptosis(Springer, 2022) Akgül, Bünyamin; Akçaöz, Azime; 01. Izmir Institute of Technology; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of ScienceApoptosis is a form of programmed cell death that is essential for cellular and organismal homeostasis. Any irregularities that disturb the balance between apoptosis and cell survival have severe implications, such as improper development or life-threatening diseases. Thus, it is highly critical to maintain a proper rate of apoptosis throughout development. In fact, several complex transcriptional and posttranscriptional mechanisms exist in eukaryotes to critically regulate the rate of apoptotic processes. Recent studies suggest that not only RNA sequences but also their modifications, such as m6A methylation, play a fundamental role in these transcriptional and posttranscriptional processes. A specific set of proteins, called writer, eraser, and reader of m6A marks, modulate the rate of apoptosis by determining the m6A repertoire and the fate of certain transcripts associated with apoptosis. In this Review, we will cover the dynamic m6A RNA modifications and their impact on modulation of apoptosis.Book Part Citation - Scopus: 86The Role of Mirna in Cancer: Pathogenesis, Diagnosis, and Treatment(Humana Press, 2022) Uzuner, Erez; Ulu, Gizem Tuğçe; Ulu, Gizem Tuğçe; Baran, Yusuf; Gürler, Sevim Beyza; Baran, Yusuf; 01.01. Units Affiliated to the Rectorate; 04.03. Department of Molecular Biology and Genetics; 01. Izmir Institute of Technology; 04. Faculty of ScienceCancer is also determined by the alterations of oncogenes and tumor suppressor genes. These gene expressions can be regulated by microRNAs (miRNA). At this point, researchers focus on addressing two main questions: “How are oncogenes and/or tumor suppressor genes regulated by miRNAs?” and “Which other mechanisms in cancer cells are regulated by miRNAs?” In this work we focus on gathering the publications answering these questions. The expression of miRNAs is affected by amplification, deletion or mutation. These processes are controlled by oncogenes and tumor suppressor genes, which regulate different mechanisms of cancer initiation and progression including cell proliferation, cell growth, apoptosis, DNA repair, invasion, angiogenesis, metastasis, drug resistance, metabolic regulation, and immune response regulation in cancer cells. In addition, profiling of miRNA is an important step in developing a new therapeutic approach for cancer. © 2022, Springer Science+Business Media, LLC, part of Springer Nature.Book Part Citation - Scopus: 20Experimental MicroRNA Detection Methods(Humana Press, 2022) Yaylak, Bilge; Akgül, Bünyamin; Akgül, Bünyamin; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMicroRNAs (miRNAs) are considerably small yet highly important riboregulators involved in nearly all cellular processes. Due to their critical roles in posttranscriptional regulation of gene expression, they have the potential to be used as biomarkers in addition to their use as drug targets. Although computational approaches speed up the initial genomewide identification of putative miRNAs, experimental approaches are essential for further validation and functional analyses of differentially expressed miRNAs. Therefore, sensitive, specific, and cost-effective microRNA detection methods are imperative for both individual and multiplex analysis of miRNA expression in different tissues and during different developmental stages. There are a number of well-established miRNA detection methods that can be exploited depending on the comprehensiveness of the study (individual miRNA versus multiplex analysis), the availability of the sample and the location and intracellular concentration of miRNAs. This review aims to highlight not only traditional but also novel strategies that are widely used in experimental identification and quantification of microRNAs. © 2022, Springer Science+Business Media, LLC, part of Springer Nature.Book Part Citation - Scopus: 94Endogenous miRNA Sponges(Humana Press, 2022) Alkan, Ayşe Hale; Akgül, Bünyamin; Akgül, Bünyamin; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyMicroRNAs (miRNAs) are a class of noncoding RNAs of 17–22 nucleotides in length with a critical function in posttranscriptional gene regulation. These master regulators are themselves subject to regulation both transcriptionally and posttranscriptionally. Recently, miRNA function has been shown to be modulated by exogenous RNA molecules that function as miRNA sponges. Interestingly, endogenous transcripts such as transcribed pseudogenes, long noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and mRNAs may serve as natural miRNA sponges. These transcripts, which bind to miRNAs and competitively sequester them away from their targets, are naturally existing endogenous miRNA sponges, called competing endogenous RNAs (ceRNAs). Here we present a historical background of miRNAs, exogenous and endogenous miRNA sponges as well as some examples of endogenous miRNA sponges involved in regulatory mechanisms associated with various diseases, developmental stages, and other cellular processes. © 2022, Springer Science+Business Media, LLC, part of Springer Nature.Article Citation - WoS: 37Mechanisms of Cellular Resistance To Imatinib in Human Chronic Myeloid Leukemia Cells(Taylor and Francis Ltd., 2007) Baran, Yusuf; Baran, Yusuf; Ural, Ali Uğur; Gündüz, Ufuk; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyA major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib, which has shown striking activity in the chronic phase and the accelerated phase, but less so in the blast phase of the disease. Despite high rates of hematologic and cytogenetic responses to therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of patients with CML. Various cellular mechanisms may be involved in the nature of cellular resistance. Increased amount of target, alteration in structure of target proteins, decreased drug uptake and increased detoxification are well-known mechanisms of resistance. On the other hand, in some cases, even if anticancer drugs reach their sites of action, bypassing drug efflux system of the cells, some cells still may survive via the dysregulation of apoptotic signalling. In this study, mechanisms of resistance to imatinib-induced apoptosis in human Meg-01 CML cells were examined. Continuous exposure of cells to step-wise increasing concentrations of imatinib resulted in the selection of 200- and 1000 nM imatinib-resistant sub-lines referred to as Meg-01/IMA-0,2 and Meg-01/1MA-1, respectively. MTT cell proliferation, cell cycle analyses and trypan blue dye exclusion analyses showed that Meg-0l/IMA-1 cells were resistant to imatinib-induced apoptosis as compared to parental sensitive cells. There was an increased expression of BCR/ABL, Bcl-2 and an increase in mitochondrial membrane potential (MMP) detected in resistant cells comparing to parental sensitive cells. There was no mutation detected in imatinib binding site of ABL kinase region. Various diverse mechanisms have been reported for their involvement in the multidrug resistance. In this study, it has been shown that the degree of BCR/ABL expression appears to be directly proportional to the levels of imatinib resistance. In addition, there have been BCR/ABL-independent mechanisms reported for deriving resistance against imatinib. Our results revealed that besides BCR/ABL overexpression, imatinib resistance also depends on the inhibition of apoptosis as a result of up-regulation of anti-apoptotic stimuli and down-regulation of pro-apoptotic stimuli through MMP but does not depend on any mutation on imatinib binding site of ABL kinase.Article Citation - WoS: 3Citation - Scopus: 4Gene Cloning, Heterologous Expression and Biochemical Characterization of a Novel Extracellular Lipase From Rhizopus Oryzae Ku45(National Institute of Genetic Engineering and Biotechnology, 2020) Arslanoğlu, Alper; Arslanoğlu, Alper; Çil, Çağlar; 04.03. Department of Molecular Biology and Genetics; 04. Faculty of Science; 01. Izmir Institute of TechnologyBackground: Lipases secreted front various Rhizopus oryzae strains were previously expressed in Escherichia coli, Pichia pastoris, and Saccharomyces cerevisiae and was shown to have distinct activities in response to different temperatures, metal ions, organic solvents, and specific substrates. However, until now, no other research biochemically characterized the functions of extracellular pro-lipase in a novel Rhizopus oryzae KU45. Objectives: Characterization of a novel extracellular lipase front fungus R. orvzae KU45 after heterologous expression in E. coli BL21 (DE3) strain. Materials and Methods: An extracellular lipase producing fungus was isolated from a soil sample and identified as a strain of R. oryzae by partial 18S rRNA gene sequencing. It was named as R. oryzae KU45. The lipase gene of KU45 was cloned into pET-28a expression vector and expressed in E. coli as inclusion bodies. The recombinant lipase was purified, refolded and characterized. Results: The lipase exhibited maximum activity at 45 degrees C, at slightly alkaline pH. It showed a broad substrate specificity acting on p-nitrophenyl esters with C-8-C-16 acyl groups as substrates and, many of the organic solvents and metal ions tested did not have any adverse effects on the enzyme activity. Conclusions: High stability, broad substrate specificity and activity at mesophilic temperatures in the presence of organic solvents, and metal ions make the extracellular lipase of KU45 a candidate for various biotechnological applications.Article Citation - WoS: 3Citation - Scopus: 4Applicability of Low-Intensity Vibrations as a Regulatory Factor on Stem and Progenitor Cell Populations(Bentham Science Publishers, 2020) Baskan, Öznur; Meşe Özçivici, Gülistan; Özçivici, Engin; Özçivici, Engin; 03.01. Department of Bioengineering; 01. Izmir Institute of Technology; 04.03. Department of Molecular Biology and Genetics; 03. Faculty of Engineering; 04. Faculty of SciencePersistent and transient mechanical loads can act as biological signals on all levels of an organism. It is therefore not surprising that most cell types can sense and respond to mechanical loads, similar to their interaction with biochemical and electrical signals. The presence or absence of mechanical forces can be an important determinant of form, function and health of many tissue types. Along with naturally occurring mechanical loads, it is possible to manipulate and apply external physical loads on tissues in biomedical sciences, either for prevention or treatment of catabolism related to many factors, including aging, paralysis, sedentary lifestyles and spaceflight. Mechanical loads consist of many components in their applied signal form such as magnitude, frequency, duration and intervals. Even though high magnitude mechanical loads with low frequencies (e.g. running or weight lifting) induce anabolism in musculoskeletal tissues, their applicability as anabolic agents is limited because of the required compliance and physical health of the target population. On the other hand, it is possible to use low magnitude and high frequency (e.g. in a vibratory form) mechanical loads for anabolism as well. Cells, including stem cells of the musculoskeletal tissue, are sensitive to high frequency, low-intensity mechanical signals. This sensitivity can be utilized not only for the targeted treatment of tissues, but also for stem cell expansion, differentiation and biomaterial interaction in tissue engineering applications. In this review, we reported recent advances in the application of low-intensity vibrations on stem and progenitor cell populations. Modulation of cellular behavior with low-intensity vibrations as an alternative or complementary factor to biochemical and scaffold induced signals may represent an increase of capabilities in studies related to tissue engineering.