And Sepsis-Induced Lung Inflammation and Mediates Myd88
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Chemoresistance in Human Ovarian Cancer: the Role of Apoptotic
Reproductive Biology and Endocrinology BioMed Central Review Open Access Chemoresistance in human ovarian cancer: the role of apoptotic regulators Michael Fraser1, Brendan Leung1, Arezu Jahani-Asl1, Xiaojuan Yan1, Winston E Thompson2 and Benjamin K Tsang*1 Address: 1Department of Obstetrics & Gynecology and Cellular & Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9, Canada and 2Department of Obstetrics & Gynecology and Cooperative Reproductive Science Research Center, Morehouse School of Medicine, Atlanta, GA 30310, USA Email: Michael Fraser - [email protected]; Brendan Leung - [email protected]; Arezu Jahani-Asl - [email protected]; Xiaojuan Yan - [email protected]; Winston E Thompson - [email protected]; Benjamin K Tsang* - [email protected] * Corresponding author Published: 07 October 2003 Received: 26 June 2003 Accepted: 07 October 2003 Reproductive Biology and Endocrinology 2003, 1:66 This article is available from: http://www.RBEj.com/content/1/1/66 © 2003 Fraser et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Recent evidence suggests that deregulation of key pro- and anti-apoptotic pathways is a key factor in the onset and maintenance of chemoresistance. Furthermore, the discovery of novel interactions between these pathways suggests that chemoresistance may be multi-factorial. Ultimately, the decision of the cancer cell to live or die in response to a chemotherapeutic agent is a consequence of the overall apoptotic capacity of that cell. -
TLR3-Dependent Activation of TLR2 Endogenous Ligands Via the Myd88 Signaling Pathway Augments the Innate Immune Response
cells Article TLR3-Dependent Activation of TLR2 Endogenous Ligands via the MyD88 Signaling Pathway Augments the Innate Immune Response 1 2, 1 3 Hellen S. Teixeira , Jiawei Zhao y, Ethan Kazmierski , Denis F. Kinane and Manjunatha R. Benakanakere 2,* 1 Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] (H.S.T.); [email protected] (E.K.) 2 Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19004, USA; [email protected] 3 Periodontology Department, Bern Dental School, University of Bern, 3012 Bern, Switzerland; [email protected] * Correspondence: [email protected] Present address: Department of Pathology, Wayne State University School of Medicine, y 541 East Canfield Ave., Scott Hall 9215, Detroit, MI 48201, USA. Received: 30 June 2020; Accepted: 12 August 2020; Published: 17 August 2020 Abstract: The role of the adaptor molecule MyD88 is thought to be independent of Toll-like receptor 3 (TLR3) signaling. In this report, we demonstrate a previously unknown role of MyD88 in TLR3 signaling in inducing endogenous ligands of TLR2 to elicit innate immune responses. Of the various TLR ligands examined, the TLR3-specific ligand polyinosinic:polycytidylic acid (poly I:C), significantly induced TNF production and the upregulation of other TLR transcripts, in particular, TLR2. Accordingly, TLR3 stimulation also led to a significant upregulation of endogenous TLR2 ligands mainly, HMGB1 and Hsp60. By contrast, the silencing of TLR3 significantly downregulated MyD88 and TLR2 gene expression and pro-inflammatory IL1β, TNF, and IL8 secretion. The silencing of MyD88 similarly led to the downregulation of TLR2, IL1β, TNF and IL8, thus suggesting MyD88 / to somehow act downstream of TLR3. -
CRKL As a Lung Cancer Oncogene and Mediator Of
views in The spotliGhT CRKL as a Lung Cancer Oncogene and Mediator of Acquired Resistance to eGFR inhibitors: is it All That it is Cracked Up to Be? Marc Ladanyi summary: Cheung and colleagues demonstrate that amplified CRKL can function as a driver oncogene in lung adeno- carcinoma, activating both RAS and RAP1 to induce mitogen-activated protein kinase signaling. In addition, they show that CRKL amplification may be another mechanism for primary or acquired resistance to epidermal growth factor re- ceptor kinase inhibitors. Cancer Discovery; 1(7); 560–1. ©2011 AACR. Commentary on Cheung et al., p. 608 (1). In this issue of Cancer Discovery, Cheung and colleagues (1) mutual exclusivity. Cheung and colleagues (1) report that present extensive genomic and functional data supporting focal CRKL amplification is mutually exclusive with EGFR focal amplification of the CRKL gene at 22q11.21 as a driver mutation and EGFR amplification. However, of the 6 lung oncogene in lung adenocarcinoma. The report expands on cancer cell lines found in this study to have focal gains of data previously presented by Kim and colleagues (2). CRKL CRKL, 2 contain other major driver oncogenes (KRAS G13D is a signaling adaptor protein that contains SH2 and SH3 in HCC515, BRAF G469A in H1755; refs. 7, 8). Interestingly, domains that mediate protein–protein interactions linking both cell lines demonstrated clear dependence on CRKL in tyrosine-phosphorylated upstream signaling molecules (e.g., functional assays. Perhaps CRKL amplification is more akin BCAR1, paxillin, GAB1) to downstream effectors (e.g., C3G, to PIK3CA mutations, which often, but not always, are con- SOS) (3). -
MYD88 L265P Is a Marker Highly Characteristic Of, but Not Restricted To, Waldenstro¨M’S Macroglobulinemia
Leukemia (2013) 27, 1722–1728 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu ORIGINAL ARTICLE MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenstro¨m’s macroglobulinemia C Jime´ nez1, E Sebastia´n1, MC Chillo´n1,2, P Giraldo3, J Mariano Herna´ndez4, F Escalante5, TJ Gonza´lez-Lo´ pez6, C Aguilera7, AG de Coca8, I Murillo3, M Alcoceba1, A Balanzategui1, ME Sarasquete1,2, R Corral1, LA Marı´n1, B Paiva1,2, EM Ocio1,2, NC Gutie´ rrez1,2, M Gonza´lez1,2, JF San Miguel1,2 and R Garcı´a-Sanz1,2 We evaluated the MYD88 L265P mutation in Waldenstro¨m’s macroglobulinemia (WM) and B-cell lymphoproliferative disorders by specific polymerase chain reaction (PCR) (sensitivity B10 À 3). No mutation was seen in normal donors, while it was present in 101/117 (86%) WM patients, 27/31 (87%) IgM monoclonal gammapathies of uncertain significance (MGUS), 3/14 (21%) splenic marginal zone lymphomas and 9/48 (19%) non-germinal center (GC) diffuse large B-cell lymphomas (DLBCLs). The mutation was absent in all 28 GC-DLBCLs, 13 DLBCLs not subclassified, 35 hairy cell leukemias, 39 chronic lymphocyticleukemias(16withM-component), 25 IgA or IgG-MGUS, 24 multiple myeloma (3 with an IgM isotype), 6 amyloidosis, 9 lymphoplasmacytic lymphomas and 1 IgM-related neuropathy. Among WM and IgM- MGUS, MYD88 L265P mutation was associated with some differences in clinical and biological characteristics, although usually minor; wild-type MYD88 cases had smaller M-component (1.77 vs 2.72 g/dl, P ¼ 0.022), more lymphocytosis (24 vs 5%, P ¼ 0.006), higher lactate dehydrogenase level (371 vs 265 UI/L, P ¼ 0.002), atypical immunophenotype (CD23 À CD27 þþFMC7 þþ), less Immunoglobulin Heavy Chain Variable gene (IGHV) somatic hypermutation (57 vs 97%, P ¼ 0.012) and less IGHV3–23 gene selection (9 vs 27%, P ¼ 0.014). -
Evidence for an Interaction Between the Insulin Receptor and Grb7. a Role for Two of Its Binding Domains, PIR and SH2
Oncogene (2000) 19, 2052 ± 2059 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Evidence for an interaction between the insulin receptor and Grb7. A role for two of its binding domains, PIR and SH2 Anne Kasus-Jacobi1,2,3,Ve ronique Be re ziat1,3, Dominique Perdereau1, Jean Girard1 and Anne-FrancËoise Burnol*,1 1Endocrinologie MeÂtabolisme et DeÂveloppement, CNRS, UPR 1524, 9 rue Jules Hetzel, 92190 Meudon, France The molecular adapter Grb7 is likely to be implicated in new family of adapters has recently emerged, the Grb7 the development of certain cancer types. In this study we family of proteins, comprising Grb7, Grb10 and show that Grb7 binds the insulin receptors, when they Grb14. The members of this family were originally are activated and tyrosine phosphorylated. This interac- cloned by interaction with EGF receptor, using the tion is documented by two-hybrid experiments, GST CORT (cloning of receptor target) system (Daly et al., pull-down assays and in vivo coimmunoprecipitations. In 1996; Margolis, 1994; Ooi et al., 1995), and the use of addition, our results argue in favor of a preferential the yeast two-hybrid technology has emphasized their association between Grb7 and the insulin receptors when implication in signal transduction (Daly, 1998). These compared to other tyrosine kinase receptors like the adapters bind also other tyrosine kinase receptors, like EGF receptor, the FGF receptor and Ret. Interestingly, erbB2, Ret, Elk, PDGF receptors, insulin receptors and Grb7 is not a substrate of the insulin receptor tyrosine IGF-1 receptors (Daly et al., 1996; Dey et al., 1996; kinase activity. -
MYD88 and Beyond: Novel Opportunities for Diagnosis, Prognosis and Treatment in Waldenstro¨M’S Macroglobulinemia
Leukemia (2014) 28, 1799–1803 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu CONCISE REVIEW MYD88 and beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenstro¨m’s Macroglobulinemia O Landgren and N Tageja Waldenstro¨m’s Macroglobulinemia (WM) is a rare disease of the elderly with a median age of 63–68 years at diagnosis. Despite recent progress in biological insights and therapeutics, WM remains clinically challenging to diagnose and is difficult to manage with significant morbidity and lack of established curative therapies. Recently, the use of whole-genome sequencing has helped to identify a highly recurrent somatic mutation, myeloid differentiation factor 88 [MYD88] L265P in WM. This has fueled major interest in the field and as newer evidence accumulates, it is clear that that discovery of MYD88 L265P mutation may represent an important breakthrough in understanding the pathogenesis of WM and lymphoproliferative disorders. Recent scientific work in this field has also guided the identification of new targets such as CXCR4 and PI3K-delta that may have major implications in the future treatment of WM. This review discusses the role of MYD88 L265P mutations as well as targets beyond MYD88 in the setting of pathogenesis and development of future rational therapeutic trials focusing on patients diagnosed with WM. Leukemia (2014) 28, 1799–1803; doi:10.1038/leu.2014.88 INTRODUCTION transduces signals to the NF-kB transcription factors in response to Waldenstro¨m’s Macroglobulinemia (WM) is a rare hematological IL-1R1 signaling. MYD88 has a modular structure with a Toll/IL-1R malignancy with a reported age-adjusted incidence rate of 3.4 per (TIR) domain at its COOH terminus and a death domain at its 12 11 million among men and 1.7 per million among women in the NH2 terminus. -
Increased in Vivo Phosphorylation of Ret Tyrosine 1062 Is a Potential Pathogenetic Mechanism of Multiple Endocrine Neoplasia Type 2B1
[CANCER RESEARCH 61, 1426–1431, February 15, 2001] Increased in Vivo Phosphorylation of Ret Tyrosine 1062 Is a Potential Pathogenetic Mechanism of Multiple Endocrine Neoplasia Type 2B1 Domenico Salvatore, Rosa Marina Melillo, Carmen Monaco, Roberta Visconti, Gianfranco Fenzi, Giancarlo Vecchio, Alfredo Fusco, and Massimo Santoro2 Centro di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare [D. S., R. M. M., C. M., R. V., G. V., M. S.], and Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Facolta` di Medicina e Chirurgia [G. F.], Universita` di Napoli “Federico II,” Naples, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Facolta`di Medicina e Chirurgia di Catanzaro, Universita`di Catanzaro, Catanzaro [A. F], Italy ABSTRACT are responsible for the inheritance of MEN2A and MEN2B and FMTC. Each disease has a distinct phenotype: MEN2A is associated Mutations of the Ret receptor tyrosine kinase are responsible for with MTC, pheochromocytoma, and parathyroid hyperplasia. The inheritance of multiple endocrine neoplasia (MEN2A and MEN2B) and MEN2B phenotype is more severe, being characterized by an earlier familial medullary thyroid carcinoma syndromes. Although several famil- ial medullary thyroid carcinoma and most MEN2A mutations involve occurrence of more aggressive MTC. Unlike MEN2A patients, substitutions of extracellular cysteine residues, in most MEN2B cases MEN2B patients develop multiple mucosal neuromas and several there is a methionine-to-threonine substitution at position 918 (M918T) of skeletal abnormalities. Finally, FMTC consists only of an inherited the Ret kinase domain. The mechanism by which the MEN2B mutation predisposition to MTC (3). Involvement of different tissues corre- converts Ret into a potent oncogene is poorly understood. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Inhibition of Mitochondrial Complex II in Neuronal Cells Triggers Unique
www.nature.com/scientificreports OPEN Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration Sathyanarayanan Ranganayaki1, Neema Jamshidi2, Mohamad Aiyaz3, Santhosh‑Kumar Rashmi4, Narayanappa Gayathri4, Pulleri Kandi Harsha5, Balasundaram Padmanabhan6 & Muchukunte Mukunda Srinivas Bharath7* Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1‑methyl‑4‑phenylpyridinium (MPP+) and 3‑nitropropionic acid (3‑NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down‑stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome‑wide transcriptomics of N27 neuronal cells exposed to 3‑NPA, compared with MPP+ and Mn revealed varied transcriptomic profle. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway diferentially regulated in the 3‑NPA model with implications for neuronal survival. This pathway was unique to 3‑NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3‑NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor -
TLR Signaling Pathways
Seminars in Immunology 16 (2004) 3–9 TLR signaling pathways Kiyoshi Takeda, Shizuo Akira∗ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan Abstract Toll-like receptors (TLRs) have been established to play an essential role in the activation of innate immunity by recognizing spe- cific patterns of microbial components. TLR signaling pathways arise from intracytoplasmic TIR domains, which are conserved among all TLRs. Recent accumulating evidence has demonstrated that TIR domain-containing adaptors, such as MyD88, TIRAP, and TRIF, modulate TLR signaling pathways. MyD88 is essential for the induction of inflammatory cytokines triggered by all TLRs. TIRAP is specifically involved in the MyD88-dependent pathway via TLR2 and TLR4, whereas TRIF is implicated in the TLR3- and TLR4-mediated MyD88-independent pathway. Thus, TIR domain-containing adaptors provide specificity of TLR signaling. © 2003 Elsevier Ltd. All rights reserved. Keywords: TLR; Innate immunity; Signal transduction; TIR domain 1. Introduction 2. Toll-like receptors Toll receptor was originally identified in Drosophila as an A mammalian homologue of Drosophila Toll receptor essential receptor for the establishment of the dorso-ventral (now termed TLR4) was shown to induce the expression pattern in developing embryos [1]. In 1996, Hoffmann and of genes involved in inflammatory responses [3]. In addi- colleagues demonstrated that Toll-mutant flies were highly tion, a mutation in the Tlr4 gene was identified in mouse susceptible to fungal infection [2]. This study made us strains that were hyporesponsive to lipopolysaccharide [4]. aware that the immune system, particularly the innate im- Since then, Toll receptors in mammals have been a major mune system, has a skilful means of detecting invasion by focus in the immunology field. -
A Synthetic Cd8a:Myd88 Coreceptor Enhances
Published OnlineFirst October 20, 2017; DOI: 10.1158/0008-5472.CAN-17-0653 Cancer Microenvironment and Immunology Research A Synthetic CD8a:MyD88 Coreceptor Enhances CD8þ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens Sabina Kaczanowska1, Ann Mary Joseph1, Jitao Guo1, Alexander K Tsai1, Jackline Joy Lasola1, Kenisha Younger1, Yuji Zhang1,2, Cruz Velasco Gonzales3, and Eduardo Davila1,4 Abstract Tcell–based immunotherapies are a promising approach for and Toll-like receptor signaling-related proteins. CD8a: patients with advanced cancers. However, various obstacles MyD88–expressing T cells improved antitumor responses in limit T-cell efficacy, including suboptimal T-cell receptor mice. Enhanced antitumor activity was associated with a (TCR) activation and an immunosuppressive tumor environ- unique tumor cytokine/chemokine signature, improved T-cell ment. Here, we developed a fusion protein by linking CD8a infiltration, reduced markers of T-cell exhaustion, elevated þ and MyD88 (CD8a:MyD88) to enhance CD8 T-cell levels of proteins associated with antigen presentation, and responses to weakly immunogenic and poorly expressed fewer macrophages with an immunosuppressive phenotype in tumor antigens. CD8a:MyD88–engineered T cells exhibited tumors. Given these observations, CD8a:MyD88 represents a increased proliferation and expression of effector and costi- unique and versatile approach to help overcome immunosup- mulatory molecules in a tumor antigen–dependent manner. pression and enhance T-cell responses to tumor antigens. These effects were accompanied by elevated activation of TCR Cancer Res; 77(24); 7049–58. Ó2017 AACR. Introduction ciated macrophage (6) and Th2 cytokine accumulation hamper antitumor T-cell responses. Moreover, chronic exposure to factors T cell–based immunotherapies are one of the most promising in the TME induces the expression of receptors that foster T-cell treatments for patients with advanced cancers, including melano- exhaustion, such as Tim-3, Lag-3, and PD-1 (7). -
Metabolic Imaging Allows Early Prediction of Response to Vandetanib
Metabolic Imaging Allows Early Prediction of Response to Vandetanib Martin A. Walter1,2,MatthiasR.Benz2,IsabelJ.Hildebrandt2, Rachel E. Laing2, Verena Hartung3, Robert D. Damoiseaux4, Andreas Bockisch3, Michael E. Phelps2,JohannesCzernin2, and Wolfgang A. Weber2,5 1Institute of Nuclear Medicine, University Hospital, Bern, Switzerland; 2Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, California; 3Institute of Nuclear Medicine, University Hospital, Essen, Germany; 4Molecular Shared Screening Resources, UCLA, Los Angeles, California; and 5Department of Nuclear Medicine, University Hospital, Freiburg, Germany The RET (rearranged-during-transfection protein) protoonco- The RET (rearranged-during-transfection protein) proto- gene triggers multiple intracellular signaling cascades regulat- oncogene, located on chromosome 10q11.2, encodes for ing cell cycle progression and cellular metabolism. We therefore a tyrosine kinase of the cadherin superfamily that activates hypothesized that metabolic imaging could allow noninvasive detection of response to the RET inhibitor vandetanib in vivo. multiple intracellular signaling cascades regulating cell sur- Methods: The effects of vandetanib treatment on the full- vival, differentiation, proliferation, migration, and chemo- genome expression and the metabolic profile were analyzed taxis (1). Gain-of-function mutations in the RET gene result in the human medullary thyroid cancer cell line TT. In vitro, tran- in uncontrolled growth and cause human cancers and scriptional changes of pathways regulating cell cycle progres- cancer syndromes, such as Hu¨rthle cell cancer, sporadic sion and glucose, dopa, and thymidine metabolism were papillary thyroid carcinoma, familial medullary thyroid correlated to the results of cell cycle analysis and the uptake of 3H-deoxyglucose, 3H-3,4-dihydroxy-L-phenylalanine, and carcinoma, and multiple endocrine neoplasia types 2A 3H-thymidine under vandetanib treatment.