Researcher:
Maiorov, Emine Güven

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PhD Student

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Emine Güven

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Maiorov

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Maiorov, Emine Güven

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2013 - 201911

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Now showing 1 - 10 of 11
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    Genome-wide RNA and DNA high throughput sequencing reveals proinflammatory and death gene signatures in head and neck squamous cell carcinoma lines with different HPV status
    (American Association for Cancer Research (AACR), 2014) Yang, Xinping; Cheng, Hui; Si, Han; Saleh, Anthony; Coupar, Jamie; Ferris, Robert L.; Yarbrough, Wendell G.; Prince, Mark E.; Carey, Thomas E.; Van Waes, Carter; Chen, Zhong; N/A; N/A; Department of Computer Engineering; N/A; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; N/A; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 26605; 8745; N/A
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    Head and neck cancers promote an inflammatory transcriptome through coactivation of classic and alternative NF-κB pathways
    (Amer Assoc Cancer Research, 2019) Yang, Xinping; Cheng, Hui; Chen, Jianhong; Wang, Ru; Saleh, Anthony; Si, Han; Lee, Steven; Nussinov, Ruth; Fang, Jugao; Van Waes, Carter; Chen, Zhong; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    Head and neck squamous cell carcinomas (HNSCC) promote inflammation in the tumor microenvironment through aberrant NF-kappa B activation, but the genomic alterations and pathway networks that modulate NF-kappa B signaling have not been fully dissected. Here, we analyzed genome and transcriptome alterations of 279 HNSCC specimens from The Cancer Genome Atlas (TCGA) cohort and identified 61 genes involved in NF-kappa B and inflammatory pathways. The top 30 altered genes were distributed across 96% of HNSCC samples, and their expression was often correlated with genomic copy-number alterations (CNA). Ten of the amplified genes were associated with human papilloma virus (HPV) status. We sequenced 15 HPV- and 11 HPV+ human HNSCC cell lines, and three oral mucosa keratinocyte lines, and supervised clustering revealed that 28 of 61 genes exhibit altered expression patterns concordant with HNSCC tissues and distinct signatures related to their HPV status. RNAi screening using an NF-kappa B reporter line identified 16 genes that are induced by TNF alpha or Lymphotoxin-beta (LT beta) and implicated in the classic and/or alternative NF-kappa B pathways. Knockdown of TNFR, LTBR, or selected downstream signaling components established cross-talk between the classic and alternative NF-kappa B pathways. TNF alpha and LT beta induced differential gene expression involving the NF-kappa B, IFN gamma, and STAT pathways, inflammatory cytokines, and metastasis-related genes. Improved survival was observed in HNSCC patients with elevated gene expression in T-cell activation, immune checkpoints, and IFN gamma and STAT pathways. These gene signatures of NF-kappa B activation, which modulate inflammation and responses to the immune therapy, could serve as potential biomarkers in future clinical trials.
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    A structural view of negative regulation of the toll-like receptor-mediated inflammatory pathway
    (Cell Press, 2015) Gursoy, Attila; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Maiorov, Emine Güven; Keskin, Özlem; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605
    Even though the Toll-like receptor (TLR) pathway is integral to inflammatory defense mechanisms, its excessive signaling may be devastating. Cells have acquired a cascade of strategies to regulate TLR signaling by targeting protein-protein interactions, or ubiquitin chains, but the details of the inhibition mechanisms are still unclear. Here, we provide the structural basis for the regulation of TLR signaling by constructing architectures of protein-protein interactions. Structural data suggest that 1) Toll/IL-1R (TIR) domain-containing regulators (BCAP, SIGIRR, and ST2) interfere with TIR domain signalosome formation; 2) major deubiquitinases such as A20, CYLD, and DUBA prevent association of TRAF6 and TRAF3 with their partners, in addition to removing K63-linked ubiquitin chains that serve as a docking platform for downstream effectors; 3) alternative downstream pathways of TLRs also restrict signaling by competing to bind common partners through shared binding sites. We also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations on the negative regulators and to observe the cellular outcome (whether there is/is not inflammation). Missense mutations that fall on interfaces and nonsense/frameshift mutations that result in truncated negative regulators disrupt the interactions with the targets, thereby enabling constitutive activation of the nuclear factor-kappa B, and contributing to chronic inflammation, autoimmune diseases, and oncogenesis.
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    The structural network of inflammation and cancer: merits and challenges
    (Academic Press Ltd- Elsevier Science Ltd, 2013) Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    Inflammation, the first line of defense against pathogens can contribute to all phases of tumorigenesis, including tumor initiation, promotion and metastasis. Within this framework, the Toll-like receptor (TLR) pathway plays a central role in inflammation and cancer. Although extremely useful, the classical representation of this, and other pathways in the cellular network in terms of nodes (proteins) and edges (interactions) is incomplete. Structural pathways can help complete missing parts of such diagrams: they demonstrate in detail how signals coming from different upstream pathways merge and propagate downstream, how parallel pathways compensate each other in drug resistant mutants, how multi-subunit signaling complexes form and in particular why they are needed and how they work, how allosteric events can control these proteins and their pathways, and intricate details of feedback loops and how kick in. They can also explain the mechanisms of some oncogenic SNP mutations. Constructing structural pathways is a challenging task. Here, our goal is to provide an overview of inflammation and cancer from the structural standpoint, focusing on the TLR pathway. We use the powerful PRISM (PRotein Interactions by Structural Matching) tool to reveal important structural information of interactions in and within key orchestrators of the TLR pathway, such as MyD88.
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    Advances in template-based protein docking by utilizing interfaces towards completing structural interactome
    (Current Biology Ltd, 2015) N/A; N/A; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 26605; 8745
    The increase in the number of structurally determined protein complexes strengthens template-based docking (TBD) methods for modelling protein-protein interactions (PPIs). These methods utilize the known structures of protein complexes as templates to predict the quaternary structure of the target proteins. The templates may be partial or complete structures. Interface based (partial) methods have recently gained interest due in part to the observation that the interface regions are reusable. We describe how available template interfaces can be used to obtain the structural models of protein interactions. Despite the agreement that a majority of the protein complexes can be modelled using the available Protein Data Bank (PDB) structures, a handful of studies argue that we need more template proteins to increase the structural coverage of PPIs. We also discuss the performance of the interface TBD methods at large scale, and the significance of capturing multiple conformations for improving accuracy.
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    Altered inflammatory and death pathways in head and neck cell lines model genomic and expression signatures identified in the cancer genome Atlas
    (American Association for Cancer Research, 2015) Yang, Xinping; Cheng, Hui; Saleh, Anthony; Cornelius, Shaleeka; Nussinov, Ruth; Van Weas, Carter; Chen, Zhong; Department of Computer Engineering; Department of Chemical and Biological Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
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    RACK1 is an interaction partner of ATG5 and a novel regulator of autophagy
    (American Society for Biochemistry and Molecular Biology (ASBMB), 2016) Erbil, Seçil; Oral, Özlem; Mitou, Geraldine; Kig, Cenk; Durmaz-Timuçin, Emel; Gülactı, Ferah; Gökçe, Gökçen; Dengjel, Jorn; Sezerman, Osman Uğur; Gözüaçık, Devrim; Department of Chemical and Biological Engineering; Maiorov, Emine Güven; Undergraduate Student; Faculty Member; Department of Chemical and Biological Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering
    Autophagy is biological mechanism allowing recycling of long-lived proteins, abnormal protein aggregates, and damaged organelles under cellular stress conditions. Following sequestration in double-or multimembrane autophagic vesicles, the cargo is delivered to lysosomes for degradation. ATG5 is a key component of an E3-like ATG12-ATG5-ATG16 protein complex that catalyzes conjugation of the MAP1LC3 protein to lipids, thus controlling autophagic vesicle formation and expansion. Accumulating data indicate that ATG5 is a convergence point for autophagy regulation. Here, we describe the scaffold protein RACK1 (receptor activated C-kinase 1, GNB2L1) as a novel ATG5 interactor and an autophagy protein. Using several independent techniques, we showed that RACK1 interacted with ATG5. Importantly, classical autophagy inducers (starvation or mammalian target of rapamycin blockage) stimulated RACK1-ATG5 interaction. Knockdown of RACK1 or prevention of its binding to ATG5 using mutagenesis blocked autophagy activation. Therefore, the scaffold protein RACK1 is a new ATG5-interacting protein and an important and novel component of the autophagy pathways.
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    The architecture of the TIR domain signalosome in the toll-like receptor-4 signaling pathway
    (Nature Publishing Group (NPG), 2015) VanWaes, Carter; Chen, Zhong; Tsai, Chung-Jung; Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; 26605; 8745
    Activated Toll-like receptors (TLRs) cluster in lipid rafts and induce pro-and anti-tumor responses. The organization of the assembly is critical to the understanding of how these key receptors control major signaling pathways in the cell. Although several models for individual interactions were proposed, the entire TIR-domain signalosome architecture has not been worked out, possibly due to its complexity. We employ a powerful algorithm, crystal structures and experimental data to model the TLR4 and its cluster. The architecture that we obtain with 8 MyD88 molecules provides the structural basis for the MyD88-templated myddosome helical assembly and receptor clustering; it also provides clues to pro-and anti-inflammatory signaling pathways branching at the signalosome level to Mal/MyD88 and TRAM/TRIF pro-and anti-inflammatory pathways. The assembly of MyD88 death domain (DD) with TRAF3 (anti-viral/anti-inflammatory) and TRAF6 (pro-inflammatory) suggest that TRAF3/TRAF6 binding sites on MyD88 DD partially overlap, as do IRAK4 and FADD. Significantly, the organization illuminates mechanisms of oncogenic mutations, demonstrates that almost all TLR4 parallel pathways are competitive and clarifies decisions at pathway branching points. The architectures are compatible with the currently-available experimental data and provide compelling insights into signaling in cancer and inflammation pathways.
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    Identification of interconnected markers for T-cell acute lymphoblastic leukemia
    (Hindawi, 2013) Ng, Özden Hatırnaz; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; N/A; 26605; 8745
    T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.
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    Structural pathways of cytokines may illuminate their roles in regulation of cancer development and immunotherapy
    (Multidisciplinary Digital Publishing Institute (MDPI), 2014) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; Maiorov, Emine Güven; Özbabacan, Saliha Ece Acuner; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; N/A; N/A; 26605; 8745
    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-?. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching-PRISM). © 2014 by the authors; licensee MDPI, Basel, Switzerland.