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Young-Lan Park, Sun-Young Park, Seung-Hyun Lee, Rul-Bin Kim, Joong-Keun Kim, Sung-Yoon Rew, Dae-Seong Myung, Sung-Bum Cho, Wan-Sik Lee, Hyun-Soo Kim, Young-Eun Joo
Filamin A interacting protein 1-like (FILIP1L) expression, which is decreased in various cancers, may inhibit carcinogenesis. In this study, we evaluated the effects of FILIP1L on oncogenic behavior and prognosis in colorectal cancer. siRNA-mediated FILIP1L knockdown enhanced tumor cell migration and invasion and inhibited apoptosis and cell cycle arrest in COLO205 cells. pcDNA-myc vector-mediated FILIP1L overexpression suppressed tumor cell migration and invasion and induced apoptosis and cell cycle arrest in HCT116 cells...
October 14, 2016: Oncotarget
Olivia Gay, Benoît Gilquin, Nicole Assard, Pascal Stuelsatz, Christian Delphin, Joël Lachuer, Xavier Gidrol, Jacques Baudier
Refilins (RefilinA and RefilinB) are members of a novel family of Filamin binding proteins that function as molecular switches to conformationally alter the Actin filament network into bundles. We show here that Refilins are extremely labile proteins. An N-terminal PEST/DSG(X)2-4S motif mediates ubiquitin-independent rapid degradation. A second degradation signal is localized within the C-terminus. Only RefilinB is protected from rapid degradation by an auto-inhibitory domain that masks the PEST/DSG(X)2-4S motif...
October 15, 2016: Biology Open
Marco Ritelli, Silvia Morlino, Edoardo Giacopuzzi, Giulia Carini, Valeria Cinquina, Nicola Chiarelli, Silvia Majore, Marina Colombi, Marco Castori
Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate...
October 14, 2016: American Journal of Medical Genetics. Part A
Juan Wang, Shasha Zhao, Yun Wei, Ying Zhou, Paul Shore, Wensheng Deng
Cytoskeletal filamin A (FLNA) is an important protein involved in multiple cellular processes. Previous studies have shown that FLNA can promote or inhibit cancer growth and development; however, the mechanisms underlying these events are not fully understood. Here we show that in both 293T and SaOS2 cells, knockdown of FLNA significantly enhanced transcription of RNA polymerase (pol) III-transcribed genes except for a subset of tRNA genes. In contrast,re-expression of FLNA in a FLNA-deficient melanoma cell line (A7) repressed transcription of all pol III-transcribed genes, suggesting that FLNA inhibits pol III transcription in a cell type-specific manner...
October 13, 2016: Journal of Biological Chemistry
Maria Elisa Perico, Silvia Grasso, Matteo Brunelli, Guido Martignoni, Enrico Munari, Enrico Moiso, Giulio Fracasso, Tiziana Cestari, Hassan Y Naim, Vincenzo Bronte, Marco Colombatti, Dunia Ramarli
The expression of Prostate Specific-Membrane Antigen (PSMA) increases in high-grade prostate carcinoma envisaging a role in growth and progression. We show here that clustering PSMA at LNCaP or PC3-PSMA cell membrane activates AKT and MAPK pathways thus promoting proliferation and survival. PSMA activity was dependent on the assembly of a macromolecular complex including filamin A, beta1 integrin, p130CAS, c-Src and EGFR. Within this complex beta1 integrin became activated thereby inducing a c-Src-dependent EGFR phosphorylation at Y1086 and Y1173 EGF-independent residues...
October 3, 2016: Oncotarget
Liang Zhang, Cuntao Yu, Qian Chang, Xinjin Luo, Juntao Qiu, Shen Liu
The aim of the present study was to compare the gene expression profiles in aortic dissection (AD) and healthy human aortic tissue samples by DNA microarray analysis in order to screen the differential genes. In total, five AD and four healthy aortic specimens were selected; the total RNA was extracted and reverse transcribed into cDNA and in vitro transcribed into aRNA, followed by microarray hybridization for analysis. Thereafter, the transcription levels of six differential genes, myosin light chain kinase (MYLK), polycystin 1, transient receptor potential channel interacting (PKD-1), myosin heavy chain 11 (MYH11), superoxide dismutase 3, extracellular (SOD3), filamin A (FLNA), and transgelin (TAGLN), screened from the expression profiles were quantitatively verified...
October 2016: Biomedical Reports
Guo-Hua Jin, Wei Xu, Yang Shi, Li-Bo Wang
Gastric cancer (GC) is a prevalent cancer, which remains incurable, and therefore requires an alternative treatment method. Celecoxib is a nonsteroidal anti-inflammatory drug that targets cyclooxygenase-2, and exhibits anticancer effects. The present study aimed to investigate the anti-GC mechanism of celecoxib using bioinformatics methods. Gene expression datasets GSE56807 (GC tissues and normal gastric tissues) and GSE54657 (celecoxib-treated and non-treated human GC epithelial AGS cells) were downloaded from the Gene Expression Omnibus database...
October 2016: Oncology Letters
Shauna L Houlihan, Alison A Lanctot, Yan Guo, Yuanyi Feng
Neuronal fate-restricted intermediate progenitors (IPs) are derived from the multipotent radial glia (RGs) and serve as the direct precursors for cerebral cortical neurons, but factors that control their neurogenic plasticity remain elusive. Here we report that IPs' neuron production is enhanced by abrogating filamin function, leading to the generation of periventricular neurons independent of normal neocortical neurogenesis and neuronal migration. Loss of Flna in neural progenitor cells (NPCs) led RGs to undergo changes resembling epithelial-mesenchymal transition (EMT) along with exuberant angiogenesis that together changed the microenvironment and increased neurogenesis of IPs...
September 24, 2016: ELife
Sied Kebir, Zacharias Orfanos, Julia Schuld, Markus Linhart, Christian Lamberz, Peter F M van der Ven, Jan Schrickel, Gregor Kirfel, Dieter O Fürst, Rainer Meyer
Pressure overload induces cardiac remodeling involving both the contractile machinery and intercalated disks (IDs). Filamin C (FlnC) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapters localizing in IDs of higher vertebrates. Knockout of the gene encoding Xin (Xirp1) in mice leads to a mild cardiac phenotype with ID mislocalization. In order to amplify this phenotype, we performed transverse aortic constriction (TAC) on control and Xirp1-deficient mice. TAC induced similar left ventricular hypertrophy in both genotypes, suggesting that the lack of Xin does not lead to higher susceptibility to cardiac overload...
October 15, 2016: Experimental Cell Research
Yiwei Wang, Shuiliang Yu, Dan Huang, Min Cui, Huankai Hu, Lihua Zhang, Weihuan Wang, Neetha Parameswaran, Mark Jackson, Barbara Osborne, Barbara Bedogni, Chaoyang Li, Man-Sun Sy, Wei Xin, Lan Zhou
Up-regulation of human prion protein (PrP) in patients with pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. However, the underlying molecular mechanism of PrP-mediated tumorigenesis is not completely understood. In this study, we found that PDAC cell lines can be divided into either PrP high expresser or PrP low expresser. In addition to filamin A (FLNA), PrP interacts with Notch1, forming a PrP/FLNA/Notch1 complex. Silencing PrP in high-expresser cells decreases Notch1 expression and Notch1 signaling...
September 14, 2016: American Journal of Pathology
D Avila-Smirnow, L Gueneau, S Batonnet-Pichon, F Delort, H-M Bécane, K Claeys, M Beuvin, B Goudeau, J-P Jais, I Nelson, P Richard, R Ben Yaou, N B Romero, K Wahbi, S Mathis, T Voit, D Furst, P van der Ven, R Gil, P Vicart, M Fardeau, G Bonne, A Behin
Myofibrillar myopathies (MFM) are mostly adult-onset diseases characterized by progressive morphological alterations of the muscle fibers beginning in the Z-disk and the presence of protein aggregates in the sarcoplasm. They are mostly caused by mutations in different genes that encode Z-disk proteins, including DES, CRYAB, LDB3, MYOT, FLNC and BAG3. A large family of French origin, presenting an autosomal dominant pattern, characterized by cardiac arrhythmia associated to late-onset muscle weakness, was evaluated to clarify clinical, morphological and genetic diagnosis...
October 2016: Revue Neurologique
Yingzi Qi, Feng Xu, Lingsheng Chen, Yanchang Li, Zhongwei Xu, Yao Zhang, Wei Wei, Na Su, Tao Zhang, Fengxu Fan, Xing Wang, Xue Qin, Lingqiang Zhang, Yinkun Liu, Ping Xu
Hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) infection is one of the most life-threatening human cancers in China. However, the pathogenesis of HCC development is still unclear. Here, we systemically analyzed liver tissues from different stages of HCC patients through 8-plex Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) approach. A total of 4,620 proteins were identified and 3,781 proteins were quantified. When T1, T2 and T3 tumor tissues were compared with T1 non-tumor cells, 330, 365 and 387 differentially expressed proteins were identified respectively...
September 9, 2016: Oncotarget
Daniela Justa-Schuch, Maria Silva-Garcia, Esther Pilla, Michael Engelke, Markus Kilisch, Christof Lenz, Ulrike Möller, Fumihiko Nakamura, Henning Urlaub, Ruth Geiss-Friedlander
The aminopeptidase DPP9 removes dipeptides from N-termini of substrates having a proline or alanine in second position. Although linked to several pathways including cell survival and metabolism, the molecular mechanisms underlying these outcomes are poorly understood. We identified a novel interaction of DPP9 with Filamin A, which recruits DPP9 to Syk, a central kinase in B-cell signalling. Syk signalling can be terminated by degradation, requiring the ubiquitin E3 ligase Cbl. We show that DPP9 cleaves Syk to produce a neo N-terminus with serine in position 1...
September 10, 2016: ELife
Eyal Reinstein, Ana Gutierrez-Fernandez, Shay Tzur, Concetta Bormans, Shai Marcu, Einav Tayeb-Fligelman, Chana Vinkler, Annick Raas-Rothschild, Dana Irge, Meytal Landau, Mordechai Shohat, Xose S Puente, Doron M Behar, Carlos Lopez-Otın
In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied whole-exome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene...
September 7, 2016: European Journal of Human Genetics: EJHG
Sven Huelsmann, Nina Rintanen, Ritika Sethi, Nicholas H Brown, Jari Ylänne
Cells integrate mechanical properties of their surroundings to form multicellular, three-dimensional tissues of appropriate size and spatial organisation. Actin cytoskeleton-linked proteins such as talin, vinculin and filamin function as mechanosensors in cells, but it has yet to be tested whether the mechanosensitivity is important for their function in intact tissues. Here we tested, how filamin mechanosensing contributes to oogenesis in Drosophila. Mutations that require more or less force to open the mechanosensor region demonstrate that filamin mechanosensitivity is important for the maturation of actin-rich ring canals that are essential for Drosophila egg development...
2016: Scientific Reports
Bo Yang, Zi Zhao Lieu, Haguy Wolfenson, Feroz M Hameed, Alexander D Bershadsky, Michael P Sheetz
To understand how cells form tissues, we need to understand how the tyrosine kinases are involved in controlling cell mechanics, whether they act directly as parts of mechanosensing machines or indirectly. Cells test the critical parameter of matrix rigidity by locally contracting ("pinching") matrices and measuring forces, and the depletion of contractile units causes transformation. We report here that knocking down the receptor tyrosine kinases (RTKs), AXL, and ROR2, alters rigidity sensing and increases the magnitude or duration of local contraction events, respectively...
September 14, 2016: Nano Letters
Pilar Cossio, Gerhard Hummer, Attila Szabo
Ductile materials can absorb spikes in mechanical force, whereas brittle ones fail catastrophically. Here we develop a theory to quantify the kinetic ductility of single molecules from force spectroscopy experiments, relating force-spike resistance to the differential responses of the intact protein and the unfolding transition state to an applied mechanical force. We introduce a class of unistable one-dimensional potential surfaces that encompass previous models as special cases and continuously cover the entire range from ductile to brittle...
August 23, 2016: Biophysical Journal
Pekka Lappalainen
The actin cytoskeleton supports a vast number of cellular processes in nonmuscle cells. It is well established that the organization and dynamics of the actin cytoskeleton are controlled by a large array of actin-binding proteins. However, it was only 40 years ago that the first nonmuscle actin-binding protein, filamin, was identified and characterized. Filamin was shown to bind and cross-link actin filaments into higher-order structures and contribute to phagocytosis in macrophages. Subsequently many other nonmuscle actin-binding proteins were identified and characterized...
August 15, 2016: Molecular Biology of the Cell
Tixieanna Dissmore, Cheikh I Seye, Denis M Medeiros, Gary A Weisman, Barry Bardford, Laman Mamedova
BACKGROUND AND AIMS: The internalization of aggregated low-density lipoproteins (agLDL) mediated by low-density lipoprotein receptor related protein (LRP1) may involve the actin cytoskeleton in ways that differ from the endocytosis of soluble LDL by the LDL receptor (LDLR). This study aims to define novel mechanisms of agLDL uptake through modulation of the actin cytoskeleton, to identify molecular targets involved in foam cell formation in vascular smooth muscle cells (VSMCs). The critical observation that formed the basis for these studies is that under pathophysiological conditions, nucleotide release from blood-derived and vascular cells activates SMC P2Y2 receptors (P2Y2Rs) leading to rearrangement of the actin cytoskeleton and cell motility...
September 2016: Atherosclerosis
Ying Jiang, Maria S Sverdlov, Peter T Toth, Long Shuang Huang, Guangwei Du, Yiyao Liu, Viswanathan Natarajan, Richard D Minshall
Caveolae are the primary route for internalization and transendothelial transport of macromolecules, such as insulin and albumin. Caveolae-mediated endocytosis is activated by Src-dependent caveolin-1 (Cav-1) phosphorylation and subsequent recruitment of dynamin-2 and filamin A (FilA), which facilitate vesicle fission and trafficking, respectively. Here, we tested the role of RalA and phospholipase D (PLD) signaling in the regulation of caveolae-mediated endocytosis and trafficking. The addition of albumin to human lung microvascular endothelial cells induced the activation of RalA within minutes, and siRNA-mediated down-regulation of RalA abolished fluorescent BSA uptake...
September 23, 2016: Journal of Biological Chemistry
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