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Daniel Aizen, Metsada Pasmanik-Chor, Rive Sarfstein, Zvi Laron, Ilan Bruchim, Haim Werner
Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively)...
2018: Frontiers in Endocrinology
Deepak Chatterjee, Lewis Lu Zhiping, Suet-Mien Tan, Surajit Bhattacharjya
Integrins are transmembrane proteins that mediate cell adhesion and migration. Each integrin is a heterodimer formed by an α and a β subunit. A large number of cytoplasmic proteins interact with the cytoplasmic tails (CTs) of integrins. The actin-binding cytoskeletal protein filamin A is a negative regulator of integrin activation. The IgFLNa21 domain of filamin A binds to the C-terminus of β2 CT that contains a TTT-motif. Based on x-ray crystallography, it has been reported that the integrin β2 CT forms a β strand that docks into the β strands C and D of IgFLNa21...
April 3, 2018: Scientific Reports
Reza Salimi, Sashidhar Bandaru, Sravani Devarakonda, Sevtap Gökalp, Chandu Ala, Ali Alvandian, Nilgün Yener, Levent M Akyürek
BACKGROUND/AIM: Filamin A (FLNA) is the most abundant and widely expressed isoform of filamin in human tissues. It is cleaved by calpain at the hinge 1 and 2 domains, producing a 90-kDa carboxyl-terminal fragment (FLNACT ). Recently, it has been shown that FLNACT mediates cell signaling and transports transcription factors into the cell nucleus. However, the significance of cleavage of FLNA by calpain has not been studied in cancer cell growth. Calpeptin is a chemical inhibitor of both calpain 1 and 2 that cleaves FLNA...
April 2018: Anticancer Research
Baikuntha Aryal, V Ashutosh Rao
Protein carbonylation is an irreversible post-translational modification induced by severe oxidative stress. Reactive oxygen species (ROS) are constantly produced in cells and play important roles in both cancer progression and cancer suppression. ROS levels can be higher in tumor compared to surrounding healthy tissue but ROS-induced specific protein carbonylation and its unique role in cancer progression or suppression is poorly understood. In this study, we utilized previously validated ELISA and western blot methods to analyze the total and specific protein carbonylation in flash-frozen human breast cancer and matched adjacent healthy tissue to compare relative total, and specific protein carbonylation...
2018: PloS One
Yilin Li, Yishuang Sun, Fuyun Sun, Rong Hua, Chenlin Li, Lang Chen, Deyin Guo, Jingfang Mu
Hepatitis B virus (HBV) infection is one of the major problems that threatens global health. There have been many studies on HBV, but the relationship between HBV and host factors is largely unexplored and more studies are needed to clarify these interactions. Filamin B is an actin-binding protein that acts as a cytoskeleton protein, and it is involved in cell development and several signaling pathways. In this study, we showed that filamin B interacted with HBV core protein, and the interaction promoted HBV replication...
March 28, 2018: Virologica Sinica
Adam C O'Neill, Christina Kyrousi, Melanie Einsiedler, Ingo Burtscher, Micha Drukker, David M Markie, Edwin P Kirk, Magdalena Götz, Stephen P Robertson, Silvia Cappello
Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor- MOB2 -in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome...
2018: Frontiers in Cellular Neuroscience
Terhi Savinko, Carla Guenther, Liisa M Uotila, Marc Llort Asens, Sean Yao, Sari Tojkander, Susanna C Fagerholm
T cells traffic from the bloodstream into tissues to perform their functions in the immune system and are therefore subjected to a range of different mechanical forces. Integrins are essential for T cell trafficking into the tissues, as they mediate firm adhesion between the T cell and the endothelium under shear flow conditions. In addition, integrins are important for the formation of the contact between the T cell and the APC required for T cell activation. The actin-binding protein filamin A (FlnA) provides an important link between the integrin and the actin cytoskeleton...
March 26, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Jennifer Karmouch, Alexandros Protonotarios, Petros Syrris
PURPOSE OF REVIEW: To date 16 genes have been associated with arrhythmogenic cardiomyopathy (ACM). Mutations in these genes can lead to a broad spectrum of phenotypic expression ranging from disease affecting predominantly the right or left ventricle, to biventricular subtypes. Understanding the genetic causes of ACM is important in diagnosis and management of the disorder. This review summarizes recent advances in molecular genetics and discusses the application of next-generation sequencing technology in genetic testing in ACM...
March 14, 2018: Current Opinion in Cardiology
Gewei Lian, Timothy Wong, Jie Lu, Jianjun Hu, Jingping Zhang, Volney Sheen
Neural progenitor proliferation and cell fate decision from self-renewal to differentiation are crucial factors in determining brain size and morphology. The cytoskeletal dependent regulation of these processes is not entirely known. The actin-binding filamin A (FlnA) was shown to regulate proliferation of progenitors by directing changes in cell cycles proteins such as Cdk1 during G2/M phase. Here we report that functional loss of FlnA not only affects the rate of proliferation by altering cell cycle length but also causes a defect in early differentiation through changes in cell fate specification...
February 16, 2018: Cerebral Cortex
Daisuke Ieda, Ikumi Hori, Yuji Nakamura, Hironori Ohshita, Yutaka Negishi, Tsutomu Shinohara, Ayako Hattori, Takenori Kato, Sachiko Inukai, Katsumasa Kitamura, Tomoki Kawai, Osamu Ohara, Shinji Kunishima, Shinji Saitoh
INTRODUCTION: Filamin A (FLNA) is located in Xq28, and encodes the actin binding protein, filamin A. A mutation in FLNA is the most common cause of periventricular nodular heterotopia (PVNH), but a clear phenotype-genotype correlation has not been established. Indeed, some patients with a FLNA mutation have recently been shown to additionally have Ehlers-Danlos-like collagenopathy or macrothrombocytopenia. In an attempt to establish a clearer correlation between clinical symptoms and genotype, we have investigated a phenotype that involves thrombocytopenia in a patient with a truncation of the FLNA gene...
February 12, 2018: Brain & Development
Lee Roth, Swati Srivastava, Moshit Lindzen, Aldema Sas-Chen, Michal Sheffer, Mattia Lauriola, Yehoshua Enuka, Ashish Noronha, Maicol Mancini, Sara Lavi, Gabi Tarcic, Gur Pines, Nava Nevo, Ori Heyman, Tamar Ziv, Oscar M Rueda, Davide Gnocchi, Eli Pikarski, Arie Admon, Carlos Caldas, Yosef Yarden
Mutations mimicking growth factor-induced proliferation and motility characterize aggressive subtypes of mammary tumors. To unravel currently unknown players in these processes, we performed phosphoproteomic analysis on untransformed mammary epithelial cells (MCF10A) that were stimulated in culture with epidermal growth factor (EGF). We identified ladinin-1 (LAD1), a largely uncharacterized protein to date, as a phosphorylation-regulated mediator of the EGF-to-ERK pathway. Further experiments revealed that LAD1 mediated the proliferation and migration of mammary cells...
January 30, 2018: Science Signaling
Arnaud Métais, Isabelle Lamsoul, Armelle Melet, Sandrine Uttenweiler-Joseph, Renaud Poincloux, Sonia Stefanovic, Amélie Valière, Anne Gonzalez de Peredo, Alexandre Stella, Odile Burlet-Schiltz, Stephane Zaffran, Pierre G Lutz, Christel Moog-Lutz
Rationale: Heart development involves differentiation of cardiac progenitors and assembly of the contractile sarcomere apparatus of cardiomyocytes. However, little is known about the mechanisms that regulate actin cytoskeleton remodeling during cardiac cell differentiation. Objective: The Asb2α Cullin5 RING E3 ubiquitin ligase triggers polyubiquitylation and subsequent degradation by the proteasome of filamins. Here, we investigate the role of Asb2α in heart development and its mechanisms of action. Methods and Results: : Using ASB2 knockout embryos, we show that Asb2 is an essential gene, critical to heart morphogenesis and function, although its loss does not interfere with the overall patterning of the embryonic heart tube...
January 26, 2018: Circulation Research
Shinya Tada, Masakazu Hamada, Yoshiaki Yura
Oncolytic herpes simplex virus type 1 (HSV-1) strain RH2 induced immunogenic cell death (ICD) with the release and surface exposure of damage-associated molecular patterns (DAMPs) in squamous cell carcinoma (SCC) SCCVII cells. The supernatants of RH2-infected SCCVII cells also exhibited antitumor ability by intratumoral administration in SCCVII tumor-bearing mice. The supernatants of RH2-infected cells and mock-infected cells were concentrated to produce Med24 and MedC for proteomic analyses. In Med24, the up- and down-regulated proteins were observed...
January 23, 2018: Cancers
Thierry Le Tourneau, Jean Mérot, Antoine Rimbert, Solena Le Scouarnec, Vincent Probst, Hervé Le Marec, Robert A Levine, Jean-Jacques Schott
Mitral valve prolapse (MVP) is a common condition that affects 2%-3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease...
January 19, 2018: Heart: Official Journal of the British Cardiac Society
Ming Hui Chen, Sangita Choudhury, Mami Hirata, Siri Khalsa, Bernard Chang, Christopher A Walsh
The cover image, by Ming Hui Chen et al., is based on the Original Article Thoracic Aortic Aneurysm in Patients with Loss of Function Filamin A Mutations: Clinical Characterization, Genetics, and Recommendations, DOI: 10.1002/ajmg.a.38580.
February 2018: American Journal of Medical Genetics. Part A
Ming Hui Chen, Sangita Choudhury, Mami Hirata, Siri Khalsa, Bernard Chang, Christopher A Walsh
The frequency and gender distribution of thoracic aortic aneurysm as a cardiovascular manifestation of loss-of-function (LOF) X-linked FilaminA (FLNA) mutations are not known. Furthermore, there is very limited cardiovascular morbidity or mortality data in children and adults. We analyzed cardiac data on the largest series of 114 patients with LOF FLNA mutations, both children and adults, with periventricular nodular heterotopia (PVNH), including 48 study patients and 66 literature patients, median age of 22...
February 2018: American Journal of Medical Genetics. Part A
Zhenfan Wang, Chen Li, Minjun Jiang, Jianchun Chen, Min Yang, Jinxian Pu
PURPOSE: This research intended to explore the effect of FLNA on cell proliferation, invasion and migration in bladder carcinoma (BC). METHODS: Microarray analysis was performed with the TCGA data, and the results were confirmed on 20 paired BC tissues and adjacent tissues using qRT-PCR and immunohistochemistry. Transmission electron microscope (TEM) and cell fluorescence assay were used to observe the quantity of autophagosomes. The expression of autophagy-related protein (LC3-I/II, p62) was detected by western blot...
February 2018: International Urology and Nephrology
Yuxia Jiao, Siqi Tan, Junyu Xiong
Sepsis is defined as life threatening organ dysfunction arising from a dysregulated host response to infection. The outcomes of sepsis include early mortality, delayed mortality and recovery, and depend on the inflammatory response. Previous studies have demonstrated that regulatory T cells (Tregs) are important in determining the outcome of sepsis, as their suppressive function serves a role in maintaining immune homeostasis. However, Treg-mediated immunosuppression during the course of sepsis remains unclear and little is known about the survival of patients following diagnosis...
December 2017: Experimental and Therapeutic Medicine
Jose J Lopez, Letizia Albarrán, Isaac Jardín, Jose Sanchez-Collado, Pedro C Redondo, Nuria Bermejo, Regis Bobe, Tarik Smani, Juan A Rosado
OBJECTIVE: Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE). APPROACH AND RESULTS: SOCE is a major mechanism for calcium influx controlled by the intracellular Ca2+ stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood...
February 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Johanna Elisabeth Emmens, Donald J L Jones, Thong H Cao, Daniel C S Chan, Simon P R Romaine, Paulene A Quinn, Stefan D Anker, John G Cleland, Kenneth Dickstein, Gerasimos Filippatos, Hans L Hillege, Chim C Lang, Piotr Ponikowski, Nilesh J Samani, Dirk J van Veldhuisen, Faiz Zannad, Aeilko H Zwinderman, Marco Metra, Rudolf A de Boer, Adriaan A Voors, Leong L Ng
AIMS: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome. METHODS AND RESULTS: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF...
February 2018: European Journal of Heart Failure
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