Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Conference Object Targeting Sphingosine Kinase-1/Spingosine-1-phosphate Receptor 2 Signalling Pathway To Overcome T315i Mutation in 32dcl3 Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Öğretmen, Besim; Baran, YusufThe main problem in chronic myeloid leukemia patients is the development of resistance against tyrosine kinase inhibitors. The expression of BCR-ABL1 having T315 mutation is responsible for the development of nilotinib resistance. The alterations in sphingolipid signalling pathway is a significant BCR-ABL1-dependent resistance mechanism. Recently, we showed that sphingosine kinase-1 (SK-1)/sphingosine-1 phosphate (S1P)-mediated drug resistance is transduced via sphingosine-1 phosphate receptor 2 (S1P2) that inhibits protein phosphatase 2A (PP2A), causing increased stability of BCR-ABL1. However, specific signaling cascade involved in this process remain unkown. In this study, BCR-ABL1 expressing 32Dcl3 cells, 32D-p210Bcr-Abl(wt) and 32D-p210Bcr-Abl (T315I) were used. The antiproliferative effects of nilotinib, SK-1 inhibitor (PF-543), S1P2 inhibitor (JTE-013), phospholipase C inhibitor (U-73122) and nilotinib/PF-543 and nilotinib/JTE-013 combinations on wt and resistant cells were determined by MTT assay. Isobologram analysis was performed using CompuSyn program.Conference Object Therapeutic Potential of Fisetin, Vitexin and Hesperetin on Chronic Myeloid Leukemia Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Baran, YusufIn Chronic Myeloid Leukemia (CML) treatment, despite therapeutic efficacy of tyrosine kinase inhibitors, resistance development and side effects cause problems. Fisetin, vitexin and hesperetin are plant-derived flavonoids. In this study, therapeutic potentials of fisetin, vitexin and hesperetin were determined in CML cells. Cytotoxic effects of flavonoids were determined by MTT assay while apoptotic effects were determined by changes in caspase- 3 activity, loss of mitochondrial membrane potential (MMP) and Annexin V/PI double staining. Cytostatic effects of the flavonoids were evaluated by propidium iodide staining using flow cytometry.Conference Object A Novel Biomarker for Drug Resistance in Chronic Myeloid Leukemia: Microrna-17(Elsevier Ltd., 2014) Baran, Yusuf; Fıratlıgil, Burcu; Kartal Yandım, Melis; Kiraz, Yağmur; Kozanoğlu, İlknur; Özdoğu, Hakan; Ünal, AlimiRNAs are single stranded small RNA molecules (20–22 nt), which do not have ability to code for proteins. These types of RNAs play significant roles on gene regulation through inhibition of their target genes. In animals, most of miRNAs show their translational inhibitor effect on target mRNAs by semi-complementation to 3’UTR sequences of mRNAs and deadenylation that cause degradation of these mRNAs. The importance of miRNAs is increasing in cancer diagnosis and treatment since they are one of the major regulators of genes such as oncogenes, tumor suppressor genes. miR-17 is an oncogenic miRNA that suppress the activation of tumor suppressor genes like CDKN1A, p21 and E2F1. Based on previous information, we aimed to determine the correlation between expression levels of miR-17 microRNA in newly diagnosed, tyrosine kinase inhibitors treated and drug resistant CML patients.Conference Object Cytotoxic and Apoptotic Effects of Fisetin, Hesperetin and Vitexinon Acute Promyelocytic Leukemia Cells(Elsevier Ltd., 2014) Adan Gökbulut, Aysun; Baran, YusufAcute Promyelocytic Leukaemia (APL) is characterized by abnormal accumulation of immature granulocytes in the bone marrow and the blood stream. To date, there is no definitive treatment strategy. Fisetin, hesperetin and vitexin are flavanoids found in fruits and vegetables. Their anticancer properties have been studied on several cancer types. In this study, we aimed to examine the cytotoxic, cytostatic and apoptotic effects of fisetin, hesperetin and vitexin on Acute Promyelocytic Leukaemia cells. Cytotoxic effects were evaluated by MTT assay while apoptotic effects of these flavonoids were examined by changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP) and Annexin V/PI double staining. Cytostatic effects of the flavonoids were evaluated by propidium iodide staining using flow cytometry.Article Citation - WoS: 15Citation - Scopus: 13Cascade Therapy With Doxorubicin and Survivin-Targeted Tailored Nanoparticles: an Effective Alternative for Sensitization of Cancer Cells To Chemotherapy(Elsevier Ltd., 2019) Dağlıoğlu, Cenk; Kacı, Fatma NecmiyeChemotherapy frequently involves combination treatment protocols to maximize tumor cell killing. Unfortunately these intensive chemotherapeutic regimes, often show disappointing results due to the development of drug resistance and higher nonspecific toxicity on normal tissues. In cancer treatment, it is critically important to minimize toxicity while preserving efficacy. We have previously addressed this issue and proposed a nanoparticle-based combination therapy involving both a molecularly targeted therapy and chemotherapeutic agent for neutralizing antiapoptotic survivin (BIRC5) to potentiate the efficacy of doxorubicin (DOX). Although the particles exhibited strong anticancer effect on the lung carcinoma A549 and the cervical carcinoma HeLa cells, there were lower-level therapeutic outcomes on the colon carcinoma HCT-116, the leukemia Jurkat and the pancreatic carcinoma MIA PaCa-2 cells. Since targeted therapies are one of the key approaches for overcoming drug resistance, tailoring the treatment of cancer cells with distinct characteristics is necessary to improve the therapeutic outcome of cancer therapy and to minimize potential pharmacokinetic interactions of drugs. In the light of this issue, this study examined whether a cascade therapy with low-dose DOX and survivin-targeted tailored nanoparticles is more effective at sensitizing HCT-116, Jurkat and MIA PaCa-2 cancer cells to DOX-chemotherapy than simultaneous combination therapy. The results demonstrated that the sequential therapy with the protocol comprising addition of the nanoparticles after incubation of cells with DOX clearly advanced the therapeutic outcome of related cancer cells, whereas the reverse protocol resulted in a reduction or delay in apoptosis, emphasizing the critical importance of formulating synergistic drug combinations in cancer therapy.Article Citation - WoS: 15Citation - Scopus: 15Identification of Stable Qtls for Fiber Quality and Plant Structure in Upland Cotton (g. Hirsutum L.) Under Drought Stress(Elsevier Ltd., 2018) Akköse Baytar, Asena; Peynircioğlu, Ceng; Sezener, Volkan; Basal, Hüseyin; Frary, Anne; Frary, Amy; Doğanlar, SamiCotton is an economically important commodity for nearly fifty industries including the textile sector which is largely based on cotton fiber. Identification of markers linked to loci for fiber traits under drought stress may be particularly beneficial because such loci could provide the genetic adaptability needed to produce good fiber under water limitation. In the present study, 177 simple sequence repeat (SSR) markers were used to detect significant quantitative trait loci (QTLs) linked to 11 fiber quality and plant structure traits in a panel of 99 Upland cotton (Gossypium hirsutum L.) genotypes using GLM and MLM analysis. The fiber quality traits, including fiber length (FL), fiber fineness (FF), fiber strength (FS), fiber elasticity (FE), fiber uniformity (FU), spinning conversion index (SCI), earliness (EAR), 1st position boll retention (1st PBR), 2nd position boll retention (2nd PBR), total boll number (TBN) and plant height (PH), were tested under both well-watered and water-limited irrigations in two locations. At both locations, GLM identified a total of 74 and 70 QTLs under well-watered and water limited conditions, respectively, at p ≤ 0.005. MLM detected seven and 23 QTLs under well-watered and water-limited conditions, respectively. Of the identified QTLs, some QTLs were detected in both locations: three for well-watered and two for water-stress conditions. Moreover, a total of 19 QTLs were stable under both watering-regimes. The QTLs identified herein could be useful in the development of cotton cultivars that have adaptability to drought conditions worldwide.Article Citation - WoS: 8Citation - Scopus: 7Secreted Wnt Antagonists in Leukemia: a Road Yet To Be Paved(Elsevier Ltd., 2018) Pehlivan, Melek; Çalışkan, Ceyda; Yüce, Zeynep; Sercan, Hakkı OgünWnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies.Article Citation - WoS: 14Citation - Scopus: 16Transcriptomic Analysis of Boron Hyperaccumulation Mechanisms in Puccinellia Distans(Elsevier Ltd., 2018) Öztürk, Saniye Elvan; Göktay, Mehmet; Has, Canan; Babaoğlu, Mehmet; Allmer, Jens; Doğanlar, Sami; Frary, AnnePuccinellia distans, common alkali grass, is found throughout the world and can survive in soils with boron concentrations that are lethal for other plant species. Indeed, P. distans accumulates very high levels of this element. Despite these interesting features, very little research has been performed to elucidate the boron tolerance mechanism in this species. In this study, P. distans samples were treated for three weeks with normal (0.5 mg L−1) and elevated (500 mg L−1) boron levels in hydroponic solution. Expressed sequence tags (ESTs) derived from shoot tissue were analyzed by RNA sequencing to identify genes up and down-regulated under boron stress. In this way, 3312 differentially expressed transcripts were detected, 67.7% of which were up-regulated and 32.3% of which were down-regulated in boron-treated plants. To partially confirm the RNA sequencing results, 32 randomly selected transcripts were analyzed for their expression levels in boron-treated plants. The results agreed with the expected direction of change (up or down-regulation). A total of 1652 transcripts had homologs in A. thaliana and/or O. sativa and mapped to 1107 different proteins. Functional annotation of these proteins indicated that the boron tolerance and hyperaccumulation mechanisms of P. distans involve many transcriptomic changes including: alterations in the malate pathway, changes in cell wall components that may allow sequestration of excess boron without toxic effects, and increased expression of at least one putative boron transporter and two putative aquaporins. Elucidation of the boron accumulation mechanism is important in developing approaches for bioremediation of boron contaminated soils.Article Citation - WoS: 4Citation - Scopus: 4Sensitive and Specific Detection of Ligands Using Engineered Riboswitches(Elsevier Ltd., 2018) Morse, Daniel P.; Nevins, Colin E.; Aggrey-Fynn, Joana Efua; Bravo, Rick J.; Pfaeffle, Herman O.I.; Laney, Jess E.Riboswitches are RNA elements found in non-coding regions of messenger RNAs that regulate gene expression through a ligand-triggered conformational change. Riboswitches typically bind tightly and specifically to their ligands, so they have the potential to serve as highly effective sensors in vitro. In B. subtilis and other gram-positive bacteria, purine nucleotide synthesis is regulated by riboswitches that bind to guanine. We modified the xpt-pbuX guanine riboswitch for use in a fluorescence quenching assay that allowed us to specifically detect and quantify guanine in vitro. Using this assay, we reproducibly detected as little as 5 nM guanine. We then produced sensors for 2′-deoxyguanosine and cyclic diguanylate (c-diGMP) by appending the P1 stem of the guanine riboswitch to the ligand-binding domains of a 2′-deoxyguanosine riboswitch and a c-diGMP riboswitch. These hybrid sensors could detect 15 nM 2′-deoxyguanosine and 3 nM c-diGMP, respectively. Each sensor retained the ligand specificity of its corresponding natural riboswitch. In order to extend the utility of our approach, we developed a strategy for the in vitro selection of sensors with novel ligand specificity. Here we report a proof-of-principle experiment that demonstrated the feasibility of our selection strategy.Book Part Citation - WoS: 30Citation - Scopus: 41Nanocarriers for Plant-Derived Natural Compounds(Elsevier Ltd., 2017) Bayraktar, Oğuz; Erdoğan, İpek; Köse, Merve D.; Kalmaz, GülcanNatural products constitute a large fraction in drug discovery processes. The term includes compounds from plants, microorganisms, and animals. Most of the natural products are secondary metabolites derived from plants, which are low in amounts and difficult to isolate. Another issue is the preservation of their bioactivity during process and storage as well as degradation in the gastrointestinal system before reaching circulation. Advances in nanotechnology offer nanoparticles, nanocapsules, and conjugates, which are devoted to site-specific, time-controlled delivery of bioactive agents. Nanoencapsulated systems have the advantage of high drug encapsulation efficiency because of optimized drug solubility in the core, low polymer content compared to other nanoparticulated systems such as nanospheres, drug polymeric shell protection against degradation factors, and the reduction of tissue irritation caused by the polymeric shell. This chapter will discuss nanoencapsulation methods and advances in carrier systems for plant-derived natural compounds.