Person: YILMAZ, BETÜL
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YILMAZ
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BETÜL
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Publication Open Access Potential role of proteasome on c-jun related signaling in hypercholesterolemia induced atherosclerosis(ELSEVIER SCIENCE BV, 2014) SÖZEN, AHMET ERDİ; Sozen, Erdi; Karademir, Betul; Yazgan, Burak; Bozaykut, Perinur; Ozer, Nesrin KartalAtherosclerosis and its complications are major causes of death all over the world. One of the major risks of atherosclerosis is hypercholesterolemia. During atherosclerosis, oxidized low density lipoprotein (oxLDL) regulates CD36-mediated activation of c-jun amino terminal kinase-1 (JNK1) and modulates matrix metalloproteinase (MMP) induction which stimulates inflammation with an invasion of monocytes. Additionally, inhibition of proteasome leads to an accumulation of c-jun and phosphorylated c-jun and activation of activator protein-1 (AP-1) related increase of MMP expression. We have previously reported a significant increase in cluster of differentiation 36 (CD36) mRNA levels in hypercholesterolemic rabbits and shown that vitamin E treatment prevented the cholesterol induced increase in CD36 mRNA expression. In the present study, our aim is to identify the signaling molecules/transcription factors involved in the progression of atherosclerosis following CD36 activation in an in vivo model of hypercholesterolemic (induced by 2% cholesterol containing diet) rabbits. In this direction, proteasomal activities by fluorometry and c-jun, phospo c-jun, JNK1, MMP-9 expressions by quantitative RT-PCR and immunoblotting were tested in aortic tissues. The effects of vitamin E on these changes were also investigated in this model. As a result, c-jun was phosphorylated following decreased proteasomal degradation in hypercholesterolemic group. MMP-9 expression was also increased in cholesterol group rabbits contributing to the development of atherosclerosis. In addition, vitamin E showed its effect by decreasing MMP-9 levels and phosphorylation of c-jun. (C) 2014 The Authors. Published by Elsevier B.V.Publication Metadata only Age-related loss of stress-induced nuclear proteasome activation is due to low PARP-1 activity(ELSEVIER SCIENCE INC, 2011) YILMAZ, BETÜL; Bakondi, Edina; Catalgol, Betul; Bak, Istvan; Jung, Tobias; Bozaykut, Perinur; Bayramicli, Mehmet; Ozer, Nesrin Kartal; Grune, TilmanChanges in protein turnover are among the dominant metabolic changes during aging. Of special importance is the maintenance of nuclear protein homeostasis to ensure a coordinated cellular metabolism. Therefore, in the nucleus a special PARP-1-mediated mechanism of proteasomal activation exists to ensure a rapid degradation of oxidized nuclear proteins. It was already demonstrated earlier that the cytosolic proteasomal system declines dramatically with aging, whereas the nuclear proteasome remains less affected. We demonstrate here that the stress-mediated proteasomal activation in the nucleus declines during replicative senescence of human fibroblasts. Furthermore, we clearly show that this decline in the PARP-1-mediated proteasomal activation is due to a decline in the expression and activity of PARP-1 in senescent fibroblasts. In a final study we show that this process also happens in vivo, because the protein expression level of PARP-1 is significantly lower in the skin of aged donors compared to that of young ones. Therefore, we conclude that the rate-limiting factor in poly(ADP-ribose)-mediated proteasomal activation in oxidative stress is PARP-1 and not the nuclear proteasome itself. (C) 2010 Elsevier Inc. All rights reserved.Publication Metadata only Proteasome inhibitors in cancer therapy: Treatment regimen and peripheral neuropathy as a side effect(ELSEVIER SCIENCE INC, 2017) YILMAZ, BETÜL; Kaplan, Gulce Sari; Torcun, Ceyda Corek; Grune, Tilman; Ozer, Nesrin Kartal; Karademir, BetulProteasomal system plays an important role in protein turnover, which is essential for homeostasis of cells. Besides degradation of oxidized proteins, it is involved in the regulation of many different signaling pathways. These pathways include mainly cell differentiation, proliferation, apoptosis, transcriptional activation and angiogenesis. Thus, proteasomal system is a crucial target for treatment of several diseases including neurodegenerative diseases, cystic fibrosis, atherosclerosis, autoimmune diseases, diabetes and cancer. Over the last fifteen years, proteasome inhibitors have been tested to highlight their mechanisms of action and used in the clinic to treat different types of cancer. Proteasome inhibitors are mainly used in combinational therapy along with classical chemo-radiotherapy. Several studies have proved their significant effects but serious side effects such as peripheral neuropathy, limits their use in required effective doses. Recent studies focus on peripheral neuropathy as the primary side effect of proteasome inhibitors. Therefore, it is important to delineate the underlying mechanisms of peripheral neuropathy and develop new inhibitors according to obtained data. This review will detail the role of proteasome inhibition in cancer therapy and development of peripheral neuropathy as a side effect. Additionally, new approaches to prevent treatment limiting side effects will be discussed in order to help researchers in developing effective strategies to overcome side effects of proteasome inhibitors.Publication Metadata only Regulation of protein turnover by heat shock proteins(ELSEVIER SCIENCE INC, 2014) YILMAZ, BETÜL; Bozaykut, Perinur; Ozer, Nesrin Kartal; Karademir, BetulProtein turnover reflects the balance between synthesis and degradation of proteins, and it is a crucial process for the maintenance of the cellular protein pool. The folding of proteins, refolding of misfolded proteins, and also degradation of misfolded and damaged proteins are involved in the protein quality control (PQC) system. Correct protein folding and degradation are controlled by many different factors, one of the most important of which is the heat shock protein family. Heat shock proteins (HSPs) are in the class of molecular chaperones, which may prevent the inappropriate interaction of proteins and induce correct folding. On the other hand, these proteins play significant roles in the degradation pathways, including endoplasmic reticulum-associated degradation (ERAD), the ubiquitin-proteasome system, and autophagy. This review focuses on the emerging role of HSPs in the regulation of protein turnover; the effects of HSPs on the degradation machineries ERAD, autophagy, and proteasome; as well as the role of posttranslational modifications in the PQC system. (C) 2014 Elsevier Inc. All rights reserved.Publication Metadata only Basic mechanisms in endoplasmic reticulum stress and relation to cardiovascular diseases(ELSEVIER SCIENCE INC, 2015) SÖZEN, AHMET ERDİ; Sozen, Erdi; Karademir, Betul; Ozer, Nesrin KartalThe folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the body to maintain this balance. Cardiovascular diseases are one of the important disorders related to failure of the UPR. Especially, protection mechanisms and the transition to apoptotic pathways have crucial roles in cardiac failure and should be highlighted in detailed studies to understand the mechanisms involved. This review is focused on the involvement of the proteasome, autophagy, and apoptosis in the UPR and the roles of these pathways in cardiovascular diseases. (C) 2014 Elsevier Inc. All rights reserved.Publication Open Access Nrf2 silencing to inhibit proteolytic defense induced by hyperthermia in HT22 cells(ELSEVIER SCIENCE BV, 2016-08) YILMAZ, BETÜL; Bozaykut, Perinur; Ozer, Nesrin Kartal; Karademir, BetulNrf2 pathway has been known to be protective against cancer progression however recent studies have revealed that the antioxidant activity of Nrf2 contributes to chemotherapy resistance. For many years, hyperthermia has been used as an additional therapy to increase the efficiency of chemotherapy and radiotherapy. Besides the positive effects of hyperthermia during treatment procedure, thermotolerance has been found to develop against heat treatment. Although the involved molecular mechanisms have not been fully clarified, heat shock proteins (HSP) and proteasome activity are known to be involved in the acquisition of thermotolerance. The aim of this study was to investigate the potential beneficial effects of combining hyperthermia with Nrf2 silencing to inhibit molecular mechanisms leading to induction of defense mechanisms in transcription level. Following heat treatment of HT22 cells, HSP70 and the proteasome levels and as well as proteasome activity were found to be elevated in the nucleus. Our results demonstrated that Nrf2 silencing reduced defense mechanisms against heat treatment both in antioxidant and proteolytic manner and Nrf2 may be a potential target for therapeutic approach in order to improve the beneficial effects of hyperthermia in cancer therapy. (C) 2016 The Authors. Published by Elsevier B.V.Publication Metadata only Endoplasmic reticulum stress and proteasomal system in amyotrophic lateral sclerosis(ELSEVIER SCIENCE INC, 2015) YILMAZ, BETÜL; Karademir, Betul; Corek, Ceyda; Ozer, Nesrin KartalProtein processing including folding, unfolding and degradation is involved in the mechanisms of many diseases. Unfolded protein response and/or endoplasmic reticulum stress are accepted to be the first steps which should be completed via protein degradation. In this direction, proteasomal system and autophagy play important role as the degradation pathways and controlled via complex mechanisms. Amyotrophic lateral sclerosis is a multifactorial neurodegenerative disease which is also known as the most catastrophic one Mutation of many different genes are involved in the pathogenesis such as superoxide dismutase 1, chromosome 9 open reading frame 72 and ubiquilin 2. These genes are mainly related to the antioxidant defense systems, endoplasmic reticulum stress related proteins and also protein aggregation, degradation pathways and therefore mutation of these genes cause related disorders. This review focused on the role of protein processing via endoplasmic reticulum and proteasomal system in amyotrophic lateral sclerosis which are the main players in the pathology. In this direction, dysfunction of endoplasmic reticulum associated degradation and related cell death mechanisms that are autophagy/apoptosis have been detailed. (C) 2015 Elsevier Inc. All rights reserved.