Β-Catenin-Mediated Wnt Signal Transduction Proceeds Through an Endocytosis-Independent Mechanism
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Integrin Adhesion Response to Chemical and Mechanical
INTEGRIN ADHESION RESPONSE TO CHEMICAL AND MECHANICAL STIMULATION A dissertation by Huang Huang Advisor: Gerald A. Meininger Ph.D Department of Medical Pharmacology and Physiology December 2017 The undersigned, appointed by the dean of the Graduate School, have examined the dissertation entitled INTEGRIN ADHESION RESPONSE TO CHEMICAL AND MECHANICAL STIMULATION Presented by Huang Huang, a candidate for the degree of doctor of philosophy of physiology, and hereby certify that, in their opinion, it is worthy of acceptance. Gerald A. Meininger Heide Schatten Michael Hill Ronald J. Korthuis ACKNOWLEGEMENTS I want to express my great respect and deep admiration to my advisor Dr. Gerald A. Meininger. He provided me the opportunity to explore this exciting research field with full support. For the past 6 years, he taught me how to think, write and work as a scientist. I am always amazed by his deep insight of research and inspired discussions with him. He is also a good friend to me with whom I can share my joys and depressions. I will miss our lunch meeting very much. I will be forever grateful for his guidance and friendship during my graduate career. I would like to thank all the members of my research committee for their help and guidance: Dr. Heide Schatten, Dr. Michael Hill, and Dr. Ronald Korthuis. I have learned a lot about science and life from them all and it is privilege to know them. Special thanks to Dr. Ronald Korthuis as Head of the Department and Dr. Allan Parrish as Director of Graduate studies. I could not complete my graduate education without their support. -
Original Article Association of AXIN2 and MMP7 Polymorphisms with Non-Small Cell Lung Cancer in Chinese Han Population
Int J Clin Exp Pathol 2016;9(2):2253-2258 www.ijcep.com /ISSN:1936-2625/IJCEP0009888 Original Article Association of AXIN2 and MMP7 polymorphisms with non-small cell lung cancer in Chinese Han population Shuguang Han, Lei Lv, Xinhua Wang, Xun Wang, Hongqing Zhao Department of Respiratory Medicine, Second People’s Hospital of Wuxi, Wuxi, Jiangsu, China Received May 4, 2015; Accepted June 23, 2015; Epub February 1, 2016; Published February 15, 2016 Abstract: Objectives: This study aimed to explore the effect of AXIN2 and MMP7 polymorphisms on non-small cell lung cancer (NSCLC) susceptibility; in addition, the interaction between gene polymorphisms and environment was also displayed. Methods: The genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 102 patients with NSCLC and 120 healthy controls. Odds ratio (OR) and 95% con- fidence interval (CI) were calculated to assess the relevance strength of AXIN2 and MMP7 polymorphisms with NSCLC. The x² test was used to compare to the frequencies difference of genotypes and alleles in cases and controls and Hardy-Weinberg equilibrium (HWE) test. The haplotype and interaction analyses were performed by haploview and MDR software, respectively. Results: The genotype frequencies of all polymorphisms in the control group conformed to HWE. GG genotype frequency of AXIN2 rs2240307 polymorphism was significantly higher in cases than controls (P=0.041). Similarly, rs2240308 in AXIN2 gene was also increased the susceptibility to NSCLC remarkably (OR=2.412, 95% CI=1.025-5.674). What’s more, haplotype A-G-G in AXIN2 might play a protective role in NSCLC (OR=0.462, 95% CI=0.270-0.790). -
Alantolactone Inhibits Cell Autophagy and Promotes Apoptosis Via AP2M1
Shi et al. Cancer Cell Int (2020) 20:442 https://doi.org/10.1186/s12935-020-01537-9 Cancer Cell International PRIMARY RESEARCH Open Access Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia Ce Shi1†, Wenjia Lan1†, Zhenkun Wang1, Dongguang Yang1, Jia Wei1, Zhiyu Liu1, Yueqiu Teng1, Mengmeng Gu2, Tian Yuan3, Fenglin Cao1, Jin Zhou2 and Yang Li1* Abstract Background: Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most com- monly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in diferent types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods: ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofuorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the efects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results: ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic efects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expres- sion. -
Integrating Protein Copy Numbers with Interaction Networks to Quantify Stoichiometry in Mammalian Endocytosis
bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Integrating protein copy numbers with interaction networks to quantify stoichiometry in mammalian endocytosis Daisy Duan1, Meretta Hanson1, David O. Holland2, Margaret E Johnson1* 1TC Jenkins Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218. 2NIH, Bethesda, MD, 20892. *Corresponding Author: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.10.29.361196; this version posted October 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract Proteins that drive processes like clathrin-mediated endocytosis (CME) are expressed at various copy numbers within a cell, from hundreds (e.g. auxilin) to millions (e.g. clathrin). Between cell types with identical genomes, copy numbers further vary significantly both in absolute and relative abundance. These variations contain essential information about each protein’s function, but how significant are these variations and how can they be quantified to infer useful functional behavior? Here, we address this by quantifying the stoichiometry of proteins involved in the CME network. We find robust trends across three cell types in proteins that are sub- vs super-stoichiometric in terms of protein function, network topology (e.g. -
APC Mutations As a Potential Biomarker for Sensitivity To
Published OnlineFirst February 8, 2017; DOI: 10.1158/1535-7163.MCT-16-0578 Companion Diagnostics and Cancer Biomarkers Molecular Cancer Therapeutics APC Mutations as a Potential Biomarker for Sensitivity to Tankyrase Inhibitors in Colorectal Cancer Noritaka Tanaka1,2, Tetsuo Mashima1, Anna Mizutani1, Ayana Sato1,3, Aki Aoyama3,4, Bo Gong3,4, Haruka Yoshida1, Yukiko Muramatsu1, Kento Nakata1,5, Masaaki Matsuura6, Ryohei Katayama4, Satoshi Nagayama7, Naoya Fujita3,4,5, Yoshikazu Sugimoto2, and Hiroyuki Seimiya1,3,5 Abstract In most colorectal cancers, Wnt/b-catenin signaling is acti- "short" truncated APCs lacking all seven b-catenin-binding vated by loss-of-function mutations in the adenomatous polyposis 20-amino acid repeats (20-AARs). In contrast, the drug-resistant coli (APC) gene and plays a critical role in tumorigenesis. cells possessed "long" APC retaining two or more 20-AARs. Knock- Tankyrases poly(ADP-ribosyl)ate and destabilize Axins, a neg- down of the long APCs with two 20-AARs increased b-catenin, ative regulator of b-catenin, and upregulate b-catenin signaling. Tcf/LEF transcriptional activity and its target gene AXIN2 expres- Tankyrase inhibitors downregulate b-catenin and are expected sion. Under these conditions, tankyrase inhibitors were able to to be promising therapeutics for colorectal cancer. However, downregulate b-catenin in the resistant cells. These results indicate colorectal cancer cells are not always sensitive to tankyrase that the long APCs are hypomorphic mutants, whereas they exert inhibitors, and predictive biomarkers for the drug sensitivity a dominant-negative effect on Axin-dependent b-catenin degra- remain elusive. Here we demonstrate that the short-form APC dation caused by tankyrase inhibitors. -
Discovery of a Novel Triazolopyridine Derivative As a Tankyrase Inhibitor
International Journal of Molecular Sciences Article Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor Hwani Ryu 1, Ky-Youb Nam 2, Hyo Jeong Kim 1, Jie-Young Song 1 , Sang-Gu Hwang 1 , Jae Sung Kim 1 , Joon Kim 3,* and Jiyeon Ahn 1,* 1 Division of Radiation Biomedical Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Korea; [email protected] (H.R.); [email protected] (H.J.K.); [email protected] (J.-Y.S.); [email protected] (S.-G.H.); [email protected] (J.S.K.) 2 Department of Research Center, Pharos I&BT Co., Ltd., Anyang 14059, Korea; [email protected] 3 Laboratory of Biochemistry, Division of Life Sciences, Korea University, Seoul 02841, Korea * Correspondence: [email protected] (J.K.); [email protected] (J.A.); Tel.: +82-2-970-1311 (J.A.) Abstract: More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2- cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized β β AXIN2, reduced active -catenin, and downregulated -catenin target genes in COLO320DM and DLD-1 cells. -
Homeostasis and Cellular Signaling
PART I Cellular Physiology CHAPTER Homeostasis and Cellular Signaling Patricia J. Gallagher, Ph.D. 11 George A. Tanner, Ph.D. CHAPTER OUTLINE ■ THE BASIS OF PHYSIOLOGICAL REGULATION ■ SECOND MESSENGER SYSTEMS AND ■ MODES OF COMMUNICATION AND SIGNALING INTRACELLULAR SIGNALING PATHWAYS ■ THE MOLECULAR BASIS OF CELLULAR SIGNALING ■ INTRACELLULAR RECEPTORS AND HORMONE ■ SIGNAL TRANSDUCTION BY PLASMA MEMBRANE SIGNALING RECEPTORS KEY CONCEPTS 1. Physiology is the study of the functions of living organisms 7. Different modes of cell communication differ in terms of and how they are regulated and integrated. distance and speed. 2. A stable internal environment is necessary for normal cell 8. Chemical signaling molecules (first messengers) provide function and survival of the organism. the major means of intercellular communication; they in- 3. Homeostasis is the maintenance of steady states in the clude ions, gases, small peptides, protein hormones, body by coordinated physiological mechanisms. metabolites, and steroids. 4. Negative and positive feedback are used to modulate the 9. Receptors are the receivers and transmitters of signaling body’s responses to changes in the environment. molecules; they are located either on the plasma mem- 5. Steady state and equilibrium are distinct conditions. brane or within the cell. Steady state is a condition that does not change over time, 10. Second messengers are important for amplification of the while equilibrium represents a balance between opposing signal received by plasma membrane receptors. forces. 11. Steroid and thyroid hormone receptors are intracellular 6. Cellular communication is essential to integrate and coor- receptors that participate in the regulation of gene ex- dinate the systems of the body so they can participate in pression. -
Mutational Analysis of AXIN2, MSX1, and PAX9 in Two Mexican Oligodontia Families
Mutational analysis of AXIN2, MSX1, and PAX9 in two Mexican oligodontia families Y.D. Mu1,2, Z. Xu1, C.I. Contreras1, J.S. McDaniel1, K.J. Donly1 and S. Chen1 1Department of Developmental Dentistry, Dental School, University of Texas Health Science Center, San Antonio, Texas, USA 2Stomotology Department, Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China Corresponding author: S. Chen E-mail: [email protected] Genet. Mol. Res. 12 (4): 4446-4458 (2013) Received July 4, 2012 Accepted May 15, 2013 Published October 10, 2013 DOI http://dx.doi.org/10.4238/2013.October.10.10 ABSTRACT. The genes for axin inhibition protein 2 (AXIN2), msh homeobox 1 (MSX1), and paired box gene 9 (PAX9) are involved in tooth root formation and tooth development. Mutations of the AXIN2, MSX1, and PAX9 genes are associated with non-syndromic oligodontia. In this study, we investigated phenotype and AXIN2, MSX1, and PAX9 gene variations in two Mexican families with non-syndromic oligodontia. Individuals from two families underwent clinical examinations, including an intra-oral examination and panoramic radiograph. Retrospective data were reviewed, and peripheral blood samples were collected. The exons and exon-intronic boundaries of the AXIN2, MSX1, and PAX9 genes were sequenced and analyzed. Protein and messenger RNA structures were predicted using bioinformative software programs. Clinical and oral examinations revealed isolated non-syndromic oligodontia in the two Mexican families. The average number of missing teeth was 12. The sequence analysis of exons and exon-intronic regions of AXIN2, MSX1, and PAX9 revealed 11 single- nucleotide polymorphisms (SNPs), including seven in AXIN2, two Genetics and Molecular Research 12 (4): 4446-4458 (2013) ©FUNPEC-RP www.funpecrp.com.br AXIN2, MSX1, and PAX9 SNPs and oligodontia 4447 in MSX1, and three in PAX9. -
Introduction to Signal Transduction
Introduction to signal transduction* Iva Greenwald§, Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, Columbia University, College of Physicians and Surgeons, New York, New York 10032 USA Signal transduction is the means by which cells respond to extracellular information. The major signaling systems have been conserved to a remarkable extent in all animals. In this first edition of Wormbook, we present chapters describing most of the major pathways for which C. elegans has played critical roles in elucidating the components, function or regulation of signal transduction. Much of the work described in these chapters illustrates the rubric, "the awesome power of C. elegans genetics". Since Sydney Brenner's initial description of C. elegans as a model organism, forward genetic approaches—screens for visible phenotypes and/or suppressors of mutant phenotypes—have identified many of the key components involved in signal transduction in all animals, and defined their diverse roles in development and cell physiology. More recently, the development of "reverse" genetic approaches that exploit the genomic sequence information, including RNA-mediated interference and screening methods to identify deletion alleles, has allowed additional signaling components to be identified and their roles to be determined. In sum, genetic analysis in C. elegans has illuminated the molecular mechanisms and biological roles of signaling systems, and has provided insights (or raised new questions) about their evolutionary origins. We start with Gerard Manning's encyclopedia of the C. elegans "kinome" (see Genomic overview of protein kinases). Protein kinases direct many cellular processes and modify the activity and localization of many cellular proteins; their centrality has made them the subject of much work in C. -
MICRURGICAL STUDIES in CELL PHYSIOLOGY. an Essential Feature
MICRURGICAL STUDIES IN CELL PHYSIOLOGY. IV. COLORIMETRIC DETERMINATION OF THE NUCLEAR AND CYTO- PLASMIC pH IN THE STARFISH EGG.* BY ROBERT CHAMBERS AND HERBERT POLLACK. (From the laboratory of Cellular Biology, Department of Anatomy, Corndl University Medical College, New York.) (Accepted for publication, February 16, 1927.) An essential feature in determining the hydrogen ion concentration of protoplasm is the maintenance of a normal condition of the proto- plasm during the procedure. Results obtained by immersing cells in solutions of dyes have been inadequate owing to the lack of satis- factory indicators to which living cells are freely permeable (1). Attempts have been made to overcome this difficulty by artificially altering the permeability of living cells (2). Any procedure, however, which exposes the cells to abnormal conditions may seriously affect the results obtained. The existence of natural dyes in the tissues has been utilized (3, 4) but has not given definite results. Some investi- gators have made bothpotentiometric and colorimetric determinations of cellular extracts (5, 6). Recently, Vl~s and his coworkers (7-10) have introduced a method (mgthode microscopiqtle d'gcrasement) by means of which echinoderm •eggs, immersed in an indicator solution, are carefully crushed between the cover slip and slide of a compressorium. As soon as the egg bursts pressure is released whereupon the dye passes in through the breaks over the surface of the egg. The objection that the pH of crushed cells may be quite different from that of the living protoplasm has already been considered by the Needhams (11). The results obtained by the micrurgical technique have brought out the importance of the plasma membrane for the maintenance of protoplasm (12-14). -
Host Cell Factors Necessary for Influenza a Infection: Meta-Analysis of Genome Wide Studies
Host Cell Factors Necessary for Influenza A Infection: Meta-Analysis of Genome Wide Studies Juliana S. Capitanio and Richard W. Wozniak Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta Abstract: The Influenza A virus belongs to the Orthomyxoviridae family. Influenza virus infection occurs yearly in all countries of the world. It usually kills between 250,000 and 500,000 people and causes severe illness in millions more. Over the last century alone we have seen 3 global influenza pandemics. The great human and financial cost of this disease has made it the second most studied virus today, behind HIV. Recently, several genome-wide RNA interference studies have focused on identifying host molecules that participate in Influen- za infection. We used nine of these studies for this meta-analysis. Even though the overlap among genes identified in multiple screens was small, network analysis indicates that similar protein complexes and biological functions of the host were present. As a result, several host gene complexes important for the Influenza virus life cycle were identified. The biological function and the relevance of each identified protein complex in the Influenza virus life cycle is further detailed in this paper. Background and PA bound to the viral genome via nucleoprotein (NP). The viral core is enveloped by a lipid membrane derived from Influenza virus the host cell. The viral protein M1 underlies the membrane and anchors NEP/NS2. Hemagglutinin (HA), neuraminidase Viruses are the simplest life form on earth. They parasite host (NA), and M2 proteins are inserted into the envelope, facing organisms and subvert the host cellular machinery for differ- the viral exterior. -
Mechanostasis in Apoptosis and Medicine
Progress in Biophysics and Molecular Biology 106 (2011) 517e524 Contents lists available at ScienceDirect Progress in Biophysics and Molecular Biology journal homepage: www.elsevier.com/locate/pbiomolbio Review Mechanostasis in apoptosis and medicine D.D. Chan a,1, W.S. Van Dyke a, M. Bahls b, S.D. Connell a, P. Critser a, J.E. Kelleher c, M.A. Kramer a, S.M. Pearce a, S. Sharma a, C.P. Neu a,* a Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, United States b Department of Health and Kinesiology, Purdue University, West Lafayette, IN 47907, United States c School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, United States article info abstract Article history: Mechanostasis describes a complex and dynamic process where cells maintain equilibrium in response Available online 8 August 2011 to mechanical forces. Normal physiological loading modes and magnitudes contribute to cell prolifera- tion, tissue growth, differentiation and development. However, cell responses to abnormal forces include Keywords: compensatory apoptotic mechanisms that may contribute to the development of tissue disease and Apoptosis pathological conditions. Mechanotransduction mechanisms tightly regulate the cell response through Programmed cell death discrete signaling pathways. Here, we provide an overview of links between pro- and anti-apoptotic Mechanobiology signaling and mechanotransduction signaling pathways, and identify potential clinical applications for Shear stress/strain Mechanotransduction treatments of disease by exploiting mechanically-linked apoptotic pathways. Ó Homeostasis 2011 Elsevier Ltd. All rights reserved. Contents 1. Introduction . .................................................517 2. Mechanostasis: tissues adapt to physical cues . ....................................518 3. Programmed cell death . .................................................519 4. Mechanotransduction and apoptosis . ............................................519 4.1.