Person: GÜLER, SABİRE
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GÜLER
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SABİRE
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Publication PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells(Springer, 2020-05-15) Özcan, Selahattin C.; Sarıoğlu, Aybike; Altunok, Tuğba H.; Akkoç, Ahmet; Güzel, Saime; Güler, Sabire; Imbert-Fernandez, Yoannis; Muchut, Robertino J.; Iglesias, Alberto A.; Gürpınar, Yunus; Clem, Amy L.; Chesney, Jason A.; Yalçın, Abdullah; Sarıoğlu, Aybike; Altunok, Tuğba H.; AKKOÇ, AHMET; GÜZEL, SAİME; GÜLER, SABİRE; Gürpınar, Yunus; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Patoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; 0000-0002-8287-6617; 0000-0003-1263-3799; 0000-0003-0796-5000; 0000-0002-7698-0872; 0000-0001-8519-8375; S-2474-2018; GCY-0775-2022; DTZ-3578-2022; AAH-4275-2021; HNI-3945-2023; ABI-4164-2020Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2's requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.Publication Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS transformed pancreatic cells(Academic Press, 2021-09-24) Özcan, Selahattin C.; Mutlu, Aydan; Altunok, Tuğba H.; Gürpınar, Yunus; Sarıoğlu, Aybike; Güler, Sabire; Muchut, Robertino J.; Iglesias, Alberto A.; Çelikler, Serap; Campbell, Paul M.; Yalçın, Abdullah; GÜLER, SABİRE; ÇELİKLER KASIMOĞULLARI, SERAP; YALÇIN, ABDULLAH; Mutlu, Aydan; Altunok, Tuğba H.; Sarıoğlu, Aybike; 0000-0003-1263-3799; 0000-0002-8287-6617; 0000-0002-4177-3478; 0000-0001-8519-8375; FNG-9051-2022; GCY-0775-2022; S-2474-2018; HTY-9355-2023; JCD-5015-2023; ABI-4164-2020Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAStransformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth. (c) 2021 Published by Elsevier Inc.Publication Effects of dietary calcium, phosphorus and microbial phytase on intestinal morphology in laying hens(TÜBİTAK, 2022-02-04) Güler, Sabire; Aşmaz, Ender Deniz; Varol Kayapunar, Nuray; İşbilir, İhsan; Cengiz, Şerife Şule; Yeşilbağ, Derya; Şanlı, Ahmet Batuhan; Gültepe, Eyüp Eren; GÜLER, SABİRE; Aşmaz, Ender Deniz; Varol Kayapunar, Nuray; İşbilir, İhsan; Cengiz, Şerife Şule; YEŞİLBAĞ, DERYA; Şanlı, Ahmet Batuhan; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Hayvan Besleme ve Beslenme Hastalıkları Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Patoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; 0000-0001-6468-8535; 0000-0002-1062-332X; 0000-0003-0708-3833; JHX-2027-2023; HPG-0648-2023; GXM-5514-2022; FCB-0607-2022; B-1526-2018; AAK-5370-2020; HJQ-8836-2023Different challenges are being applied in poultrthe y industry in order to protect animal health and to increase immunity and production. The supplementation of microbial phytase is essential in terms of both reducing the inorganic phytase rate and contributing to the absorption of other minerals. In this study, a newly isolated microbial phytase was added at different concentrations to the diet together with calcium (Ca2+) and available phosphorus (AP), and the effects of this supplementation on intestinal absorption capacity and Ca2+ binding capacity were investigated via morphological measurements and immunohistochemical examination of the duodenum and ileum. For this purpose, 90 Lohmann LSL-White laying hens were divided into three main diet groups: 1. Standard Ca2+ and AP (Ca+AP), 2. Standard Ca2+ and low AP (Ca+low AP), and 3. Low Ca2+ and low AP (low Ca+low AP). These three groups were further divided into three phytase subgroups each (without phytase [Phy-], commercial phytase [CP] and microbial phytase [MP]). At the end of the experiment, animals were euthanized, and duodenum and ileum samples were fixed and processed for histological examination. Villus height, crypt depth, total mucosa thickness, and villus width were measured and villus height: crypt depth ratio and villus absorption area were calculated. Caldesmon expression in the duodenum and ileum was also investigated immunohistochemically. The results indicated that villus height, total mucosa thickness, and villus absorption area increased (p <= 0.05) in birds fed with Ca2+ APIMP. Stronger caldesmon expression was observed in the MP treated groups. We concluded that MP produced from Bacillus megaterium EBD 9-1 bacterium increases the utilization of Ca2+ and AP and, thus, can have a beneficial role when these macrominerals are used insufficiently. Ca2+, AP, and MP may have positive effects on the intestinal morphology and absorption area when used at optimum amounts.Publication Overexpression of dual-specificity phosphatases 4 and 13 attenuates transforming growth factor β1-induced migration and drug resistance in A549 cells in vitro(Academic Press Inc Elsevier Science, 2022-03-23) Güler, Sabire; Altunok, Tuğba H.; Sarıoğlu, Aybike; Zik, Berrin; Aşmaz, Deniz; Kayapunar, Nuray; Sönmez, Öner; Tepedelen, Burcu Erbaykent; Yalçın, Abdullah; GÜLER, SABİRE; Altunok, Tuğba H.; Sarıoğlu, Aybike; ZIK, BERRİN; Aşmaz, Deniz; Kayapunar, Nuray; SÖNMEZ, ÖNER; Tepedelen, Burcu Erbaykent; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı.; Bursa Uludağ Üniversitesi/Fen-Edebiyat Fakültesi/Moleküler Biyoloji ve Genetik Anabilim Dalı.; 0000-0002-7367-6859; 0000-0003-1263-3799; 0000-0002-1062-332X; 0000-0001-8519-8375; 0000-0002-8287-6617; 0000-0001-6468-8535; AAH-8807-2021; KMY-2643-2024; S-2474-2018; AAH-9810-2021; HPG-0648-2023; GXM-5514-2022; DTN-7054-2022; AAH-6436-2021; ABI-4164-2020Transforming growth factor-beta (TGF beta) proteins induce an epithelial-mesenchymal transition (EMT) programme that is associated with increased invasive and drug-resistant phenotype of carcinoma cells. In addition to the canonical pathway involving SMAD proteins, the mitogen-activated kinase (MAPK) pathway via extracellular signal-regulated kinases 1/2 (ERK1/2) is also involved in promoting and maintaining a mesenchymal phenotype by tumor cells following TGF beta signal activation. As dual-specificity phosphatases (DUSPs) regulate ERK1/2 activity by dephosphorylation, we aimed to examine DUSPs' expression upon TGF beta stimulation and whether DUSPs play a role in the EMT and related phenotypes promoted by TGF beta 1 in A549 cells. We found that TGF beta 1 stimulation led to marked changes in several DUSP proteins, including significant decreases in DUSP4 and DUSP13 expressions. We then showed that the ectopic co-expression of DUSP4/13 suppresses TGF beta 1-induced ERK1/2 phosphorylation and protein levels of the EMT transcription factors Snail and Slug proteins. We then demonstrated that DUSP4/13 co-expression partially inhibited TGF beta 1-promoted migration, invasion, and chemoresistance in A549 cells. Collectively, this report provides data for the involvement of DUSP4/13 in malignant phenotypes regulated by TGF beta 1 in A549 cells. (C) 2022 Elsevier Inc. All rights reserved.Publication Upregulation of dual-specificity phosphatase-26 is required for transforming growth factor β1(TGFβ1)-induced Epithelial-mesenchymal transition in A549 and PANC1 cells(Springer, 2022-09-02) Güler, Sabire; Zık, Berrin; Yalçın, Abdullah; GÜLER, SABİRE; ZIK, BERRİN; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Biyokimya Anabilim Dalı.; 0000-0002-7367-6859; 0000-0001-8519-8375; AAH-9810-2021; ABI-4164-2020; AAH-8807-2021; A-5261-2016Background Transforming Growth Factor beta (TGF beta) proteins are potent inducers of the epithelial-mesenchymal transition (EMT) in tumor cells. Although mitogen-activated protein kinase (MAPK) family has been shown to be involved in TGF beta-induced EMT, role of Dual Specificity Phosphatases (DUSP), key regulators of MAPK activity, in TGF beta-induced EMT is largely unkonwn.Methods and results Real-time qPCR analyses were performed to determine the effect of TGF beta 1 on expression of EMT genes and DUSP proteins in the non-small cell lung cancer model A549 and pancreatic adenocarcinoma model PANC1 cells. Western blot analyses were conducted to study the changes in protein levels of EMT proteins and select DUSP proteins, as well as phosphorylations of MAPK proteins upon TGF beta 1 stimulation. Small interfering RNA (siRNA) was utilized to reduce expressions of DUSP genes. We observed that the EMT phenotype coincided with increases in phosphorylations of the MAPK proteins ERK1/2, p38MAPK, and JNK upon TGF beta 1 stimulation. Real-time qPCR analysis showed increases in DUSP15 and DUSP26 mRNA levels and Western blot analysis confirmed the increase in DUSP26 protein levels in both A549 and PANC1 cells treated with TGF beta 1 relative to control. Silencing of DUSP26 expression by siRNA markedly suppressed the effect of TGF beta 1 on E-cadherin and mesenchymal genes in the cells.Conclusions Data provided suggest that TGF beta 1 modulates the expression of DUSP genes and that upregulation of DUSP26 may be required for TGF beta 1-promoted EMT in A549 and PANC1 cells. Further studies should be carried out to elucidate the requirement of individual DUSPs in TGF beta 1-associated EMT in tumor cells.Publication Expression of dual-specifiicity phosphatases in tgfss1-induced emt in skov3 cells(Tubitak Scientific & Technological Research Council Turkey, 2023-01-01) Güler, Sabire; GÜLER, SABİRE; Yalçın, Abdullah; YALÇIN, ABDULLAH; Bursa Uludağ Üniversitesi/Veteriner Fakültesi/Histoloji ve Embriyoloji Anabilim Dalı.Background/aim: The study aims to profile the dual-specificity phosphatases (DUSP) expression in response to Transforming growth factor (31 (TGF(31)-induced epithelial-mesenchymal transition (EMT) in ovarian adenocarcinoma cells.Materials and methods: The ovarian adenocarcinoma cell line SKOV3 was used as a TGF(31-induced EMT model. Cells were incubated with 5 ng/mL TGF(31 to induce EMT. EMT was confirmed with real-time qPCR, western blot, and immunofluorescence analyses of various EMT markers. Western blot was used to analyze phospho-and total MAPK protein levels. Typical and atypical DUSPs mRNA expression profile was determined by real-time qPCR.Results: The epithelial marker E-cadherin expressions were decreased and mesenchymal EMT markers Snail and Slug expression levels were increased after TGF(31 induction. Phosphorylation of ERK1/2 and p38 MAPK were enhanced in response to TGF(31 treatment. The expression of DUSP2, DUSP6, DUSP8, DUSP10, and DUSP13 were decreased while DUSP7, DUSP16, DUSP18, DUSP21, and DUSP27 were increased by TGF(31.Conclusion: TGF(31 induced EMT which was accompanied by increased activity of MAPKs, and led to marked changes in expressions of several DUSPs in SKOV3 cells.