Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - WoS: 4Citation - Scopus: 4Interferon Gamma-Inducible Nampt in Melanoma Cells Serves as a Mechanism of Resistance To Enhance Tumor Growth(MDPI, 2023) Barba, Cindy; Ekiz, Hüseyin Atakan; Tang, William Weihao; Ghazaryan, Arevik; Hansen, Mason; Lee, Soh-Hyun; Voth, Warren PeterSimple Summary The tumor microenvironment is complex, with interacting immune and tumor cells. Immune cells release inflammatory cytokines, including interferons (IFNs), that drive tumor clearance. However, evidence suggests that tumor cells can also utilize IFNs to enhance growth and survival in certain cases. We demonstrate that interferon gamma (IFN gamma) mediates the metabolic reprogramming of melanoma cells by inducing the essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene through STAT1 binding to the NAMPT locus. NAMPT is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and increased NAMPT. We show that IFN gamma signaling upregulates NAMPT in melanoma cells, increasing cell proliferation and survival. Further, STAT1-inducible Nampt promotes melanoma growth in mice. We provide evidence that melanoma cells directly respond to IFN gamma-activated STAT1 by increasing Nampt, which improves their fitness during tumor immunity. Elucidating mechanisms that regulate NAMPT expression can lead to enhanced therapeutic approaches with immunotherapies that utilize IFN signaling to improve patient outcomes. (1) Background: Immune cells infiltrate the tumor microenvironment and secrete inflammatory cytokines, including interferons (IFNs), to drive antitumor responses and promote tumor clearance. However, recent evidence suggests that sometimes, tumor cells can also harness IFNs to enhance growth and survival. The essential NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) gene is constitutively expressed in cells during normal homeostasis. However, melanoma cells have higher energetic demands and elevated NAMPT expression. We hypothesized that interferon gamma (IFN gamma) regulates NAMPT in tumor cells as a mechanism of resistance that impedes the normal anti-tumorigenic effects of IFN gamma. (2) Methods: Utilizing a variety of melanoma cells, mouse models, Crispr-Cas9, and molecular biology techniques, we explored the importance of IFN gamma-inducible NAMPT during melanoma growth. (3) Results: We demonstrated that IFN gamma mediates the metabolic reprogramming of melanoma cells by inducing Nampt through a Stat1 binding site in the Nampt gene, increasing cell proliferation and survival. Further, IFN/STAT1-inducible Nampt promotes melanoma in vivo. (4) Conclusions: We provided evidence that melanoma cells directly respond to IFN gamma by increasing NAMPT levels, improving their fitness and growth in vivo (control n = 36, SBS KO n = 46). This discovery unveils a possible therapeutic target that may improve the efficacy of immunotherapies involving IFN responses in the clinic.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, RakiebMature 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.Article Citation - WoS: 14Citation - Scopus: 16Plaqview 2.0: a Comprehensive Web Portal for Cardiovascular Single-Cell Genomics(Frontiers Media S.A., 2022) Ma, Wei Feng; Turner, Adam W.; Gancayco, Christina; Wong, Doris; Song, Yipei; Mosquera, Jose Verdezoto; Auguste, Gaëlle; Hodonsky, Chani J.; Prabhakar, Ajay; Ekiz, Hüseyin Atakan; van der Laan, Sander W.; Miller, Clint L.Single-cell RNA-seq (scRNA-seq) is a powerful genomics technology to interrogate the cellular composition and behaviors of complex systems. While the number of scRNA-seq datasets and available computational analysis tools have grown exponentially, there are limited systematic data sharing strategies to allow rapid exploration and re-analysis of single-cell datasets, particularly in the cardiovascular field. We previously introduced PlaqView, an open-source web portal for the exploration and analysis of published atherosclerosis single-cell datasets. Now, we introduce PlaqView 2.0 (www.plaqview.com), which provides expanded features and functionalities as well as additional cardiovascular single-cell datasets. We showcase improved PlaqView functionality, backend data processing, user-interface, and capacity. PlaqView brings new or improved tools to explore scRNA-seq data, including gene query, metadata browser, cell identity prediction, ad hoc RNA-trajectory analysis, and drug-gene interaction prediction. PlaqView serves as one of the largest central repositories for cardiovascular single-cell datasets, which now includes data from human aortic aneurysm, gene-specific mouse knockouts, and healthy references. PlaqView 2.0 brings advanced tools and high-performance computing directly to users without the need for any programming knowledge. Lastly, we outline steps to generalize and repurpose PlaqView's framework for single-cell datasets from other fields.Article Citation - WoS: 9Citation - Scopus: 11Mir-Aculous New Avenues for Cancer Immunotherapy(Frontiers Media S.A., 2022) Tang, William W.; Bauer, Kaylyn M.; Barba, Cindy; Ekiz, Hüseyin Atakan; O’Connell, Ryan M.The rising toll of cancer globally necessitates ingenuity in early detection and therapy. In the last decade, the utilization of immune signatures and immune-based therapies has made significant progress in the clinic; however, clinical standards leave many current and future patients without options. Non-coding RNAs, specifically microRNAs, have been explored in pre-clinical contexts with tremendous success. MicroRNAs play indispensable roles in programming the interactions between immune and cancer cells, many of which are current or potential immunotherapy targets. MicroRNAs mechanistically control a network of target genes that can alter immune and cancer cell biology. These insights provide us with opportunities and tools that may complement and improve immunotherapies. In this review, we discuss immune and cancer cell–derived miRNAs that regulate cancer immunity and examine miRNAs as an integral part of cancer diagnosis, classification, and therapy.Article Citation - WoS: 27Citation - Scopus: 27Epithelial-Myeloid Exchange of Mhc Class Ii Constrains Immunity and Microbiota Composition(Elsevier, 2021) Stephens, W. Zac; Kubinak, Jason L.; Ghazaryan, Arevik; Bauer, Kaylyn M.; Buhrke, Kate; Round, June L.; Ekiz, Hüseyin AtakanIntestinal epithelial cells (IECs) have long been understood to express high levels of major histocompatibility complex class II (MHC class II) molecules but are not considered canonical antigen-presenting cells, and the impact of IEC-MHC class II signaling on gut homeostasis remains enigmatic. As IECs serve as the primary barrier between underlying host immune cells, we reasoned that IEC-intrinsic antigen presentation may play a role in responses toward the microbiota. Mice with an IEC-intrinsic deletion of MHC class II (IECΔMHC class II) are healthy but have fewer microbial-bound IgA, regulatory T cells (Tregs), and immune repertoire selection. This was associated with increased interindividual microbiota variation and altered proportions of two taxa in the ileum where MHC class II on IECs is highest. Intestinal mononuclear phagocytes (MNPs) have similar MHC class II transcription but less surface MHC class II and are capable of acquiring MHC class II from IECs. Thus, epithelial-myeloid interactions mediate development of adaptive responses to microbial antigens within the gastrointestinal tract.Article Citation - WoS: 33Citation - Scopus: 35Imatinib Induces Autophagy Through Beclin-1 and Atg5 Genes in Chronic Myeloid Leukemia Cells(Taylor and Francis Ltd., 2011) Can, Geylani; Ekiz, Hüseyin Atakan; Baran, YusufLocate full-text(opens in a new window)|Full Text(opens in a new window)|View at Publisher| Export | Download | Add to List | More... Hematology Volume 16, Issue 2, March 2011, Pages 95-99 Imatinib induces autophagy through BECLIN-1 and ATG5 genes in chronic myeloid leukemia cells (Article) Can, G., Ekiz, H.A., Baran, Y. Department of Molecular Biology and Genetics, Faculty of Science, Izmir Institute of Technology, 35430 Urla, Izmir, Turkey View references (35) Abstract Imatinib is a chemotherapeutic drug used for the treatment of chronic myeloid leukemia (CML). Recent data showed imatinib-induced cell death in various types of cancers. Autophagy is the physiological process in which cellular components are broken down by the lysosomal activation. In this study, we aimed to examine the effects of imatinib on autophagy in addition to apoptosis in CML cells. Results suggested that imatinib induces autophagy in CML cells through inducing over-expression of BECLIN-1 and ATG5 genes with the statistical significance. Our results demonstrated that autophagy might be involved in imatinib-induced cell death.Article Citation - WoS: 6Citation - Scopus: 6Bioactive Sphingolipids in Response To Chemotherapy: a Scope on Leukemias(Bentham Science Publishers B.V., 2011) Ekiz, Hüseyin Atakan; Baran, YusufSphingolipids are major constituents of the cells with emerging roles in the regulation of cellular processes. Deregulation of sphingolipid metabolism is reflected as various pathophysiological conditions including metabolic disorders and several forms of cancer. Ceramides, ceramide-1-phosphate (C1P), glucosyl ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P) are among the bioactive sphingolipid species that have important roles in the regulation of cell death, survival and chemotherapeutic resistance. Some of those species are known to accumulate in the cells upon chemotherapy while some others are known to exhibit an opposite pattern. Even though the length of fatty acid chain has a deterministic effect, in general, upregulation of ceramides and sphingosine is known to induce apoptosis. However, S1P, C1P and GluCer are proliferative for cells and they are involved in the development of chemoresistance. Therefore, sphingolipid metabolism appears as a good target for the development of novel therapeutics or supportive interventions to increase the effectiveness of the chemotherapeutic drugs currently in hand. Some approaches involve manipulation of the synthesis pathways yielding the increased production of apoptotic sphingolipids while the proliferative ones are suppressed. Some others are trying to take advantage of cytotoxic sphingolipids like short chain ceramide analogs by directly delivering them to the malignant cells as a distinct chemotherapeutic intervention. Numerous studies in the literature show the feasibility of those approaches especially in acute and chronic leukemias. This review compiles the current knowledge about sphingolipids and their roles in chemotherapeutic response with the particular attention to leukemias. © 2011 Bentham Science Publishers Ltd.Article Citation - WoS: 4Citation - Scopus: 7The Importance of Protein Profiling in the Diagnosis and Treatment of Hematologic Malignancies(Galenos Yayıncılık, 2011) Şanlı Mohamed, Gülşah; Turan, Taylan; Ekiz, Hüseyin Atakan; Baran, YusufProteins are important targets in cancer research because malignancy is associated with defects in cell protein machinery. Protein profiling is an emerging independent subspecialty of proteomics that is rapidly expanding and providing unprecedented insight into biological events. Quantitative assessment of protein levels in hematologic malignancies seeks a comprehensive understanding of leukemiaassociated protein patterns for use in aiding diagnosis, follow-up treatment, and the prediction of clinical outcomes. Many recently developed high-throughput proteomic methods can be applied to protein profiling. Herein the importance of protein profiling, its exploitation in leukemia research, and its clinical usefulness in the treatment and diagnosis of various cancer types, and techniques for determining changes in protein profiling are reviewed.Article Citation - WoS: 31Citation - Scopus: 36Quercetin-Induced Apoptosis Involves Increased Htert Enzyme Activity of Leukemic Cells(Taylor and Francis Ltd., 2011) Avcı, Çığır Biray; Yılmaz, Sunde; Doğan, Zeynep Özlem; Saydam, Güray; Dodurga, Yavuz; Ekiz, Hüseyin Atakan; Kartal, Melis; Şahin, Fahri; Baran, Yusuf; Gündüz, CumhurWe aimed to examine the growth suppressive effects of quercetin on acute promyelocytic and lymphoblastic leukemia and chronic myeloid leukemia, and to find out whether the growth suppression is related to the blocking of telomerase enzyme activity. Cytotoxic effects of quercetin were shown by trypan blue analyses. Apoptotic effects of quercetin were examined by acridine orange and ethidium bromide staining by fluorescence microscopy. The effects of quercetin on telomerase enzyme activity were shown by hTERT Quantification Kit. Our results demonstrated that quercetin has antiproliferative and apoptotic effects on T-cell acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia, and chronic myeloid leukemia (CML) cells. We also showed for the first time by this study that quercetin suppresses the activity of telomerase in ALL and CML cells. The results of this study show the importance of quercetin for its therapeutic potential in treatment of leukemias.Article Citation - WoS: 23Citation - Scopus: 25Role of Autophagy in the Progression and Suppression of Leukemias(Elsevier Ltd., 2012) Ekiz, Hüseyin Atakan; Can, Geylani; Baran, YusufAutophagy is a physiological process in which cellular components are degraded by the lysosomal machinery. Thereby, organelles are recycled and monomers are produced in order to maintain energy production. Current studies indicate autophagy might suppress or augment survival of cancer cells. Therefore, by elucidating the role of autophagy in cancer pathogenesis, novel therapeutic intervention points may be revealed. Leukemia therapy has advanced in recent years; but a definitive cure is still lacking. Since autophagy often is deregulated in this particular type of cancer, it is clear that future findings will have clinical implications. This review will discuss the current knowledge of autophagy in blood cancers. © 2011 Elsevier Ireland Ltd.