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Dive into the research topics where Feyza Engin is active.

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Featured researches published by Feyza Engin.


Nature Medicine | 2008

Dimorphic effects of Notch signaling in bone homeostasis

Feyza Engin; Zhenqiang Yao; Tao Yang; Guang Zhou; Terry Bertin; Ming Ming Jiang; Yuqing Chen; Lisa Wang; Hui Zheng; Richard E. Sutton; Brendan F. Boyce; Brendan Lee

Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.


Proceedings of the National Academy of Sciences of the United States of America | 2006

Dominance of SOX9 function over RUNX2 during skeletogenesis

Guang Zhou; Qiping Zheng; Feyza Engin; Elda Munivez; Yuqing Chen; Eiman Sebald; Deborah Krakow; Brendan Lee

Mesenchymal stem cell-derived osteochondroprogenitors express two master transcription factors, SOX9 and RUNX2, during condensation of the skeletal anlagen. They are essential for chondrogenesis and osteogenesis, respectively, and their haploinsufficiency causes human skeletal dysplasias. We show that SOX9 directly interacts with RUNX2 and represses its activity via their evolutionarily conserved high-mobility-group and runt domains. Ectopic expression of full-length SOX9 or its RUNX2-interacting domain in mouse osteoblasts results in an osteodysplasia characterized by severe osteopenia and down-regulation of osteoblast differentiation markers. Thus, SOX9 can inhibit RUNX2 function in vivo even in established osteoblastic lineage. Finally, we demonstrate that this dominant inhibitory function of SOX9 is physiologically relevant in human campomelic dysplasia. In campomelic dysplasia, haploinsufficiency of SOX9 results in up-regulation of the RUNX2 transcriptional target COL10A1 as well as all three members of RUNX gene family. In summary, SOX9 is dominant over RUNX2 function in mesenchymal precursors that are destined for a chondrogenic lineage during endochondral ossification.


Diabetes, Obesity and Metabolism | 2010

Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases.

Feyza Engin; Gökhan S. Hotamisligil

The endoplasmic reticulum (ER) is a eukaryotic organelle that plays important roles in protein synthesis, folding and trafficking, calcium homoeostasis and lipid and steroid synthesis. It is the major protein synthesis compartment for secreted, plasma membrane and organelle proteins. Perturbations of ER homeostasis such as the accumulation of unfolded or misfolded proteins cause ER stress. To alleviate this stress, ER triggers an evolutionarily conserved signalling cascade called the unfolded protein response (UPR). As an initial response, the UPR aims at adapting and restoring ER function by translational attenuation, upregulation of ER chaperones and degradation of unfolded proteins. However, if the ER function is severely impaired because of excessive or prolonged exposure to stress, then the inflicted cells may undergo programmed cell death. During ER stress, unstable or partially folded mutant proteins are prevented from trafficking to their proper subcellular localizations and usually rapidly degraded. The small molecules named chemical chaperones help to stabilize these mutant proteins and facilitate their folding and proper trafficking from the ER to their final destinations. Because increasing number of studies suggest that ER stress is involved in a number of disease pathogenesis including neurodegenerative diseases, cancer, obesity, diabetes and atherosclerosis, promoting ER folding capacity through chemical chaperones emerges as a novel therapeutic approach. In this review, we provide insight into the many important functions of chemical chaperones during ER stress, their impact on the ER‐stress‐related pathologies and their potential as a new drug targets, especially in the context of metabolic disorders.


Human Molecular Genetics | 2009

Notch signaling contributes to the pathogenesis of human osteosarcomas

Feyza Engin; Terry Bertin; Ou Ma; Ming Ming Jiang; Lisa Wang; Richard E. Sutton; Lawrence A. Donehower; Brendan Lee

Notch signaling plays an important role in developmental processes and adult tissue homeostasis. Altered Notch signaling has been associated with various diseases including cancer. While the importance of altered Notch signaling in cancers of hematopoietic and epithelial origins has been established, its role in tumors of mesenchymal origin is less clear. Here, we report that human osteosarcoma cell lines and primary human osteosarcoma tumor samples show significant up-regulation of Notch, its target genes and Osterix. Notch inhibition by gamma-secretase inhibitors or by using lentiviral mediated expression of dominant negative Mastermind-like protein (DN-MAML) decreases osteosarcoma cell proliferation in vitro. In vivo, established human tumor xenografts in nude mice show decreased tumor growth after chemical or genetic inhibition of Notch signaling. Finally, transcriptional profiling of osteosarcomas from p53 mutant mice confirmed up-regulation of Notch1 target genes Hes1, Hey1 and its ligand Dll4. Our data suggest that activation of Notch signaling contributes to the pathogenesis of human osteosarcomas and its inhibition may be a therapeutic approach for the treatment of this mesenchymal tumor.


Science Translational Medicine | 2013

Restoration of the Unfolded Protein Response in Pancreatic β Cells Protects Mice Against Type 1 Diabetes

Feyza Engin; Alena Yermalovich; Truc Nguyen; Sarah Hummasti; Wenxian Fu; Decio L. Eizirik; Diane Mathis; Gökhan S. Hotamisligil

Preservation of insulin-producing pancreatic β cells in type 1 diabetes requires an intact UPR, and treatment with tauroursodeoxycholic acid can restore UPR defects. Performance Enhancement The stress response can help raise a person’s performance level at crucial times—when meeting a cougar on a hike, dancing Swan Lake for the first time, or teaching your teen to drive. But chronic stress strains the body and mind in unhealthy ways. This principle holds true at the molecular level. When organs place a high demand on the cell’s endoplasmic reticulum (ER) for proper synthesis, folding, and trafficking of large amounts of protein, misfolded or unfolded proteins can accumulate in the ER and trigger the unfolded protein response (UPR). The UPR is a complex program that drives either proper folding of misfolded proteins via chaperones or degradation of these proteins to restore ER homeostasis. This adaptation to ER stress is beneficial in acute situations but detrimental under chronic pathological conditions. Indeed, recent research illustrates the importance of restoring ER homeostasis in type 2 diabetes (T2D) and neurodegenerative disorders. Now, Engin et al. investigate ER stress in the context of autoimmune (type 1) diabetes (T1D). Tweaks in ER homeostasis are known to spur stress responses that modify glucose and lipid metabolism. But little is known about the role of the UPR in the natural history of T1D or in the disease’s characteristic dysfunction and death of pancreatic β cells. These cells play a central role in initiating carbohydrate metabolism by secreting insulin in response to glucose intake. The authors uncovered defects in the expression of two UPR mediators, ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1), in pancreatic β cells from T1D patients and two distinct mouse models of T1D. When the mice were treated at the prediabetic stage with tauroursodeoxycholic acid (TUDCA)—a bile acid produced by the liver and known to quell ER stress—diabetes incidence was significantly reduced in an ATF6-dependent manner. The treated mice also displayed decreased infiltration of autoimmune-associated lymphocytes in the pancreas and increased survival, insulin secretion, and UPR-mediator expression in pancreatic β cells. The data show that, in mouse models of T1D, a functional UPR participates in the preservation of pancreatic β cells and that UPR dysfunction can be prevented with TUDCA therapy. Currently, autoantibody testing permits the identification of human T1D patients one to two years before they develop symptoms. Therefore, this study suggests a strategy for preventing aberrant ER function in prediabetic autoantibody-positive patients. Further, a clinical (safety) trial for the TUDCA precursor UDCA was initiated for patients with Huntington’s disease (NCT00514774), a neurological disorder that is associated with protein misfolding and aggregation and might involve a dysfunctional UPR. Thus reversing stressful conditions in the ER might have wide-ranging therapeutic consequences. Perturbations in endoplasmic reticulum (ER) homeostasis can evoke stress responses leading to aberrant glucose and lipid metabolism. ER dysfunction is linked to inflammatory disorders, but its role in the pathogenesis of autoimmune type 1 diabetes (T1D) remains unknown. We identified defects in the expression of unfolded protein response (UPR) mediators ATF6 (activating transcription factor 6) and XBP1 (X-box binding protein 1) in β cells from two different T1D mouse models and then demonstrated similar defects in pancreatic β cells from T1D patients. Administration of a chemical ER stress mitigator, tauroursodeoxycholic acid (TUDCA), at the prediabetic stage resulted in a marked reduction of diabetes incidence in the T1D mouse models. This reduction was accompanied by (i) a significant decrease in aggressive lymphocytic infiltration in the pancreas, (ii) improved survival and morphology of β cells, (iii) reduced β cell apoptosis, (iv) preserved insulin secretion, and (v) restored expression of UPR mediators. TUDCA’s actions were dependent on ATF6 and were lost in mice with β cell–specific deletion of ATF6. These data indicate that proper maintenance of the UPR is essential for the preservation of β cells and that defects in this process can be chemically restored for preventive or therapeutic interventions in T1D.


Bone | 2010

NOTCHing the bone: insights into multi-functionality.

Feyza Engin; Brendan Lee

Evolutionarily conserved Notch signaling plays a critical role during embryonic and postnatal life. The importance of Notch signaling in the determination of cell fate, and the spatio-temporal regulation of proliferation, differentiation and apoptosis has been demonstrated in various different organ systems. However, how Notch signaling affects the bone development was unknown until now. The in vivo effects of Notch signaling in lineage commitment, bone formation and bone resorption were demonstrated in recent studies. In addition to regulation of osteoblastogenesis, osteoblast directed osteoclastogenesis by Notch signaling revealed a dimorphic effect for this signaling pathway providing another example of such in bone development. Moreover, identification of the cross talk between the hematopoietic stem cell niche and osteoblasts through Notch signaling also suggested another important role for Notch signaling, i.e., the coupling of cellular components of the bone microenvironment. The association between the gain and loss of function of Notch activity in bone pathology highlights Notch as a potentially novel therapeutic target for the treatment of metabolic bone disease and bone cancer. In this review, we will focus primarily on the regulation of bone cells, i.e., osteoblasts and osteoclasts by Notch signaling. We will also review the importance of Notch in specifying bone-hematopoietic stem cell niche interactions within the bone microenvironment. Finally, we will discuss potential clinical implications and future directions for this field.


Diabetologia | 2015

Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms

Flora Brozzi; Tarlliza R. Nardelli; Miguel Lopes; Isabelle Millard; Jenny Barthson; Mariana Igoillo-Esteve; Fabio Arturo Grieco; Olatz Villate; Joana Moitinho Oliveira; Marina Casimir; Marco Bugliani; Feyza Engin; Gökhan S. Hotamisligil; Piero Marchetti; Decio L. Eizirik

Aims/hypothesisProinflammatory cytokines contribute to beta cell damage in type 1 diabetes in part through activation of endoplasmic reticulum (ER) stress. In rat beta cells, cytokine-induced ER stress involves NO production and consequent inhibition of the ER Ca2+ transporting ATPase sarco/endoplasmic reticulum Ca2+ pump 2 (SERCA2B). However, the mechanisms by which cytokines induce ER stress and apoptosis in mouse and human pancreatic beta cells remain unclear. The purpose of this study is to elucidate the role of ER stress on cytokine-induced beta cell apoptosis in these three species and thus solve ongoing controversies in the field.MethodsRat and mouse insulin-producing cells, human pancreatic islets and human EndoC-βH1 cells were exposed to the cytokines IL-1β, TNF-α and IFN-γ, with or without NO inhibition. A global comparison of cytokine-modulated gene expression in human, mouse and rat beta cells was also performed. The chemical chaperone tauroursodeoxycholic acid (TUDCA) and suppression of C/EBP homologous protein (CHOP) were used to assess the role of ER stress in cytokine-induced apoptosis of human beta cells.ResultsNO plays a key role in cytokine-induced ER stress in rat islets, but not in mouse or human islets. Bioinformatics analysis indicated greater similarity between human and mouse than between human and rat global gene expression after cytokine exposure. The chemical chaperone TUDCA and suppression of CHOP or c-Jun N-terminal kinase (JNK) protected human beta cells against cytokine-induced apoptosis.Conclusions/interpretationThese observations clarify previous results that were discrepant owing to the use of islets from different species, and confirm that cytokine-induced ER stress contributes to human beta cell death, at least in part via JNK activation.


Scientific Reports | 2015

Aberrant islet unfolded protein response in type 2 diabetes.

Feyza Engin; Truc Nguyen; Alena Yermalovich; Gökhan S. Hotamisligil

The endoplasmic reticulum adapts to fluctuations in demand and copes with stress through an adaptive signaling cascade called the unfolded protein response (UPR). Accumulating evidence indicates that the canonical UPR is critical to the survival and function of insulin-producing pancreatic β-cells, and alterations in the UPR may contribute to the pathogenesis of type 2 diabetes. However, the dynamic regulation of UPR molecules in the islets of animal models and humans with type 2 diabetes remains to be elucidated. Here, we analyzed the expression of activating factor 6 (ATF6α) and spliced X-box binding protein 1 (sXBP1), and phosphorylation of eukaryotic initiation factor 2 (eIF2α), to evaluate the three distinct branches of the UPR in the pancreatic islets of mice with diet- or genetic-induced obesity and insulin resistance. ATF6 and sXBP1 expression was predominantly found in the β-cells, where hyperglycemia coincided with a decline in expression in both experimental models and in humans with type 2 diabetes. These data suggest alterations in the expression of UPR mediators may contribute to the decline in islet function in type 2 diabetes in mice and humans.


Journal of Clinical Investigation | 2010

E-selectin ligand-1 regulates growth plate homeostasis in mice by inhibiting the intracellular processing and secretion of mature TGF-β

Tao Yang; Roberto Mendoza-Londono; Huifang Lu; Jianning Tao; Kaiyi Li; Bettina Keller; Ming Ming Jiang; Rina Shah; Yuqing Chen; Terry Bertin; Feyza Engin; Branka Dabovic; Daniel B. Rifkin; John Hicks; Milan Jamrich; Arthur L. Beaudet; Brendan Lee

The majority of human skeletal dysplasias are caused by dysregulation of growth plate homeostasis. As TGF-beta signaling is a critical determinant of growth plate homeostasis, skeletal dysplasias are often associated with dysregulation of this pathway. The context-dependent action of TFG-beta signaling is tightly controlled by numerous mechanisms at the extracellular level and downstream of ligand-receptor interactions. However, TGF-beta is synthesized as an inactive precursor that is cleaved to become mature in the Golgi apparatus, and the regulation of this posttranslational intracellular processing and trafficking is much less defined. Here, we report that a cysteine-rich protein, E-selectin ligand-1 (ESL-1), acts as a negative regulator of TGF-beta production by binding TGF-beta precursors in the Golgi apparatus in a cell-autonomous fashion, inhibiting their maturation. Furthermore, ESL-1 inhibited the processing of proTGF-beta by a furin-like protease, leading to reduced secretion of mature TGF-beta by primary mouse chondrocytes and HEK293 cells. In vivo loss of Esl1 in mice led to increased TGF-beta/SMAD signaling in the growth plate that was associated with reduced chondrocyte proliferation and delayed terminal differentiation. Gain-of-function and rescue studies of the Xenopus ESL-1 ortholog in the context of early embryogenesis showed that this regulation of TGF-beta/Nodal signaling was evolutionarily conserved. This study identifies what we believe to be a novel intracellular mechanism for regulating TGF-beta during skeletal development and homeostasis.


Journal of Investigative Medicine | 2015

ER stress and development of type 1 diabetes

Feyza Engin

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

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Brendan Lee

Baylor College of Medicine

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Ming Ming Jiang

Baylor College of Medicine

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Terry Bertin

Baylor College of Medicine

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Yuqing Chen

Baylor College of Medicine

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