WoS İndeksli Yayınlar Koleksiyonu / WoS Indexed Publications Collection
Permanent URI for this collectionhttps://hdl.handle.net/11147/7150
Browse
18 results
Search Results
Conference Object Suppression of STAT5A Increases Chemotherapeutic Sensitivity in Imatinib-Resistant and Imatinib-Sensitive K562 Cells(Ferrata Storti Foundation, 2010) Baran, Y.; Baran, Yusuf; Kosova, B.; Ekiz, Hüseyin Atakan; Tezcanli, B.; Ekiz, H.; Cakir, Z.; Selvi, S.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.; Hu, R.; Huffaker, T.B.; Ramstead, A.G.; Ekiz, Hüseyin Atakan; Bauer, K.M.; Tang, W.W.The 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: 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.Conference Object Nilotinib Significantly Induces Apoptosis in Imatinib Resistant K562 Cells, as Effectively as in Parental Sensitive Counterparts(Ferrata Storti Foundation, 2009) Baran, Yusuf; Can, Geylani; Ekiz, Hüseyin Atakan[No abstract available]Conference Object Imatinib Induces Autophagy Through Increasing the Expression Levels of Beclin-1 and Atg-5 Genes in Both Parental Sensitive and Imatinib-Resistant K562 Cells(Ferrata Storti Foundation, 2009) Baran, Yusuf; Can, Geylani; Ekiz, Hüseyin Atakan; Genç, S. G.[No abstract available]Conference Object The Roles of Stat Transcription Factors in Imatinib Resistance and Sensitivity in Bcr/Abl Positive Chronic Myeloid Leukemia Cells(Elsevier Ltd., 2010) Baran, Yusuf; Kosova, Buket; Tezcanlı, Burçin; Ekiz, Hüseyin Atakan; Çakır, Zeynep; Selvi, Nur[No abstract available]