Digital Commons Network^™

Deubiquitinase Usp47/Ubp64e Regulates Β-Catenin Ubiquitination And Degradation And Plays A Positive Role In Wnt Signaling, Jiandang Shi, Yajuan Liu, Xuehe Xu, Wen Zhang, Tianxin Yu, Jianhang Jia, Chunming Liu

Markey Cancer Center Faculty Publications

Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, …

Time From Infection To Disease And Infectiousness For Ebola Virus Disease, A Systematic Review, Gustavo E Velásquez, Omowunmi Aibana, Emilia J Ling, Ibrahim Diakite, Eric Q Mooring, Megan B Murray

Faculty, Staff and Student Publications

We systematically reviewed the literature to estimate the incubation and latent periods of Ebola virus disease. We found limited epidemiological data from individuals with discrete 1-day exposures. Available data suggest that the incubation and latent periods may differ, and mathematical models may be improved by distinguishing between the two periods.

Caffeine And Progression Of Parkinson Disease: A Deleterious Interaction With Creatine., David K. Simon, Cai Wu, Barbara C. Tilley, Anne-Marie Wills, Michael J. Aminoff, Jacquelyn Bainbridge, Robert A. Hauser, Jay S. Schneider, Saloni Sharma, Carlos Singer, Caroline M. Tanner, Daniel Truong, Pei Shieen Wong

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVE: Increased caffeine intake is associated with a lower risk of Parkinson disease (PD) and is neuroprotective in mouse models of PD. However, in a previous study, an exploratory analysis suggested that, in patients taking creatine, caffeine intake was associated with a faster rate of progression. In the current study, we investigated the association of caffeine with the rate of progression of PD and the interaction of this association with creatine intake.

METHODS: Data were analyzed from a large phase 3 placebo-controlled clinical study of creatine as a potentially disease-modifying agent in PD. Subjects were recruited for this study from …

Mechanistic Insights Into Glucan Phosphatase Activity Against Polyglucan Substrates, David A. Meekins, Madushi Raththagala, Kyle D. Auger, Benjamin D. Turner, Diana Santelia, Oliver Kötting, Matthew S. Gentry, Craig W. Vander Kooi

Molecular and Cellular Biochemistry Faculty Publications

Glucan phosphatases are central to the regulation of starch and glycogen metabolism. Plants contain two known glucan phosphatases, Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2), which dephosphorylate starch. Starch is water-insoluble and reversible phosphorylation solubilizes its outer surface allowing processive degradation. Vertebrates contain a single known glucan phosphatase, laforin, that dephosphorylates glycogen. In the absence of laforin, water-soluble glycogen becomes insoluble, leading to the neurodegenerative disorder Lafora Disease. Because of their essential role in starch and glycogen metabolism glucan phosphatases are of significant interest, yet a comparative analysis of their activities against diverse glucan substrates has not been established. …

Role And Regulation Of Coordinately Expressed De Novo Purine Biosynthetic Enzymes Ppat And Paics In Lung Cancer, Moloy T. Goswami, Guoan Chen, Balabhadrapatruni Chakravarthi, Satya Pathi, Sharath Anand, Shannon Carskadon, Thomas Giordano, Arul Chinnaiyan, Dafydd Thomas, Nallasivam Palanisamy, David Beer, Sooryanarayana Varambally

Urology Articles

Cancer cells exhibit altered metabolism including aerobic glycolysis that channels several glycolytic intermediates into de novo purine biosynthetic pathway. We discovered increased expression of phosphoribosyl amidotransferase (PPAT) and phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) enzymes of de novo purine biosynthetic pathway in lung adenocarcinomas. Transcript analyses from next-generation RNA sequencing and gene expression profiling studies suggested that PPAT and PAICS can serve as prognostic biomarkers for aggressive lung adenocarcinoma. Immunohistochemical analysis of PAICS performed on tissue microarrays showed increased expression with disease progression and was significantly associated with poor prognosis. Through gene knockdown and over-expression studies we demonstrate that altering …

Gm1 Ganglioside In Parkinson's Disease: Pilot Study Of Effects On Dopamine Transporter Binding., Jay S. Schneider, Franca Cambi, Stephen M. Gollomp, Hiroto Kuwabara, James R. Brašić, Benjamin E. Leiby, Stephanie Sendek, Dean F. Wong

Department of Pharmacology and Experimental Therapeutics Faculty Papers

OBJECTIVE: GM1 ganglioside has been suggested as a treatment for Parkinson's disease (PD), potentially having symptomatic and disease modifying effects. The current pilot imaging study was performed to examine effects of GM1 on dopamine transporter binding, as a surrogate measure of disease progression, studied longitudinally.

METHODS: Positron emission tomography (PET) imaging data were obtained from a subset of subjects enrolled in a delayed start clinical trial of GM1 in PD [1]: 15 Early-start (ES) subjects, 14 Delayed-start (DS) subjects, and 11 Comparison (standard-of-care) subjects. Treatment subjects were studied over a 2.5 year period while Comparison subjects were studied over 2 …

Development And Validation Of An Epitope Prediction Tool For Swine (Pigmatrix) Based On The Pocket Profile Method, Andres H. Gutiérrez, William D. Martin, Chris Bailey-Kellogg, Frances Terry, Leonard Moise, Anee S. De Groot

Dartmouth Scholarship

Background: T cell epitope prediction tools and associated vaccine design algorithms have accelerated the development of vaccines for humans. Predictive tools for swine and other food animals are not as well developed, primarily because the data required to develop the tools are lacking. Here, we overcome a lack of T cell epitope data to construct swine epitope predictors by systematically leveraging available human information. Applying the “pocket profile method ”, we use sequence and structural similarities in the binding pockets of human and swine major histocompatibility complex proteins to infer Swine Leukocyte Antigen (SLA) peptide binding preferences. We developed epitope-prediction …

Targeting Ezh2 Regulates Tumor Growth And Apoptosis Through Modulating Mitochondria Dependent Cell-Death Pathway In Hnscc, Xuan Zhou, Yu Ren, Lingping Kong, Guoshuai Cai, Shanshan Sun, Wangzhao Song, Yu Wang, Rui Jin, Lisha Qi, Mei Mei

Dartmouth Scholarship

EZH2 is a negative prognostic factor and is overexpressed or activated in most human cancers including head and neck squamous cell carcinoma (HNSCC). Analysis of The Cancer Genome Atlas (TCGA) HNSCC data indicated that EZH2 over-expression was associated with high tumor grade and conferred poor prognosis. EZH2 inhibition triggered cell apoptosis, cell cycle arrest and decreased cell growth in vitro. MICU1 (mitochondrial calcium uptake1) was shown to be down regulated when EZH2 expression was inhibited in HNSCC. When the EZH2 and MICU1 were inhibited, HNSCC cells became susceptible to cell cycle arrest and apoptosis. Mitochondrial membrane potential and cytosolic Ca2+ …

Autophagy Is Induced Upon Platelet Activation And Is Essential For Hemostasis And Thrombosis, Madhu M. Ouseph, Yunjie Huang, Meenakshi Banerjee, Smita Joshi, Laura Macdonald, Yu Zhong, Huijuan Liu, Xianting Li, Binggang Xiang, Guoying Zhang, Masaaki Komatsu, Zhenyu Yue, Zhenyu Li, Brian Storrie, Sidney W. Whiteheart, Qing Jun Wang

Molecular and Cellular Biochemistry Faculty Publications

Autophagy is important for maintaining cellular homeostasis, and thus its deficiency is implicated in a broad spectrum of human diseases. Its role in platelet function has only recently been examined. Our biochemical and imaging studies demonstrate that the core autophagy machinery exists in platelets, and that autophagy is constitutively active in resting platelets. Moreover, autophagy is induced upon platelet activation, as indicated by agonist-induced loss of the autophagy marker LC3II. Additional experiments, using inhibitors of platelet activation, proteases, and lysosomal acidification, as well as platelets from knockout mouse strains, show that agonist-induced LC3II loss is a consequence of platelet signaling …

The Role Of Perlecan And Endorepellin In The Control Of Tumor Angiogenesis And Endothelial Cell Autophagy., Stephen Douglass, Atul Goyal, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

During tumor growth and angiogenesis there is a dynamic remodeling of tissue architecture often accompanied by the release of extracellular matrix constituents full of biological activity. One of the key constituents of the tumor microenvironment is the large heparan sulfate proteoglycan perlecan. This proteoglycan, strategically located at cell surfaces and within basement membranes, is a well-defined pro-angiogenic molecule when intact. However, when partially processed by proteases released during cancer remodeling and invasion, the C-terminal fragment of perlecan, known as endorepellin, has opposite effects than its parent molecule. Endorepellin is a potent inhibitor of angiogenesis by exerting a dual receptor antagonism …

How Clinicians Feel About Working With Spouses Of The Chronically Ill, Douglas Ingram

NYMC Faculty Publications

Clinicians who provide psychotherapy to spouses or partners of the chronically ill were solicited through listserves of psychodynamic and other organizations. The current report excluded those therapists working with spouses of dementia patients. Interviews were conducted with clinicians who responded. The interviews highlight the challenges commonly encountered by psychotherapeutic work with this cohort of therapy patients. A comparison is drawn that shows both overlap and distinctions between the experiences of those therapists engaging with spouses of chronically ill patients without a dementing process and those working with spouses of chronically ill patients who do suffer from a dementing process.

Delivery Of Nucleic Acids And Nanomaterials By Cell-Penetrating Peptides: Opportunities And Challenges, Yue-Wern Huang, Han-Jung Lee, Larry Tolliver, Robert Aronstam

Biological Sciences Faculty Research & Creative Works

Many viral and nonviral systems have been developed to aid delivery of biologically active molecules into cells. Among these, cell-penetrating peptides (CPPs) have received increasing attention in the past two decades for biomedical applications. In this review, we focus on opportunities and challenges associated with CPP delivery of nucleic acids and nanomaterials. We first describe the nature of versatile CPPs and their interactions with various types of cargoes. We then discuss in vivo and in vitro delivery of nucleic acids and nanomaterials by CPPs. Studies on the mechanisms of cellular entry and limitations in the methods used are detailed.

Finding The Engram., Sheena A Josselyn, Stefan Köhler, Paul W Frankland

Brain and Mind Institute Researchers' Publications

Many attempts have been made to localize the physical trace of a memory, or engram, in the brain. However, until recently, engrams have remained largely elusive. In this Review, we develop four defining criteria that enable us to critically assess the recent progress that has been made towards finding the engram. Recent 'capture' studies use novel approaches to tag populations of neurons that are active during memory encoding, thereby allowing these engram-associated neurons to be manipulated at later times. We propose that findings from these capture studies represent considerable progress in allowing us to observe, erase and express the engram.

Positional Differences In Reactive Hyperemia Provide Insight Into Initial Phase Of Exercise Hyperemia., Jeffrey L Jasperse, J Kevin Shoemaker, Eric J Gray, Philip S Clifford

Kinesiology Publications

Studies have reported a greater blood flow response to muscle contractions when the limb is below the heart compared with above the heart, and these results have been interpreted as evidence for a skeletal muscle pump contribution to exercise hyperemia. If limb position affects the blood flow response to other vascular challenges such as reactive hyperemia, this interpretation may not be correct. We hypothesized that the magnitude of reactive hyperemia would be greater with the limb below the heart. Brachial artery blood flow (Doppler ultrasound) and blood pressure (finger-cuff plethysmography) were measured in 10 healthy volunteers. Subjects lay supine with …

Erbb3-Erbb2 Complexes As A Therapeutic Target In A Subset Of Wild-Type Braf/Nras Cutaneous Melanomas., Claudia Capparelli, Sheera Rosenbaum, Lisa D. Berman-Booty, Amel Salhi, Nadège Gaborit, Tingting Zhan, Inna Chervoneva, Jason Roszik, Scott E. Woodman, Michael A. Davies, Yulius Y. Setiady, Iman Osman, Yosef Yarden, Andrew E. Aplin

Department of Cancer Biology Faculty Papers

The treatment options remain limited for patients with melanoma who are wild-type for both BRAF and NRAS (WT/WT). We demonstrate that a subgroup of WT/WT melanomas display high basal phosphorylation of ErbB3 that is associated with autocrine production of the ErbB3 ligand neuregulin-1 (NRG1). In WT/WT melanoma cells displaying high levels of phospho-ErbB3, knockdown of NRG1 reduced cell viability and was associated with decreased phosphorylation of ErbB3, its coreceptor ErbB2, and its downstream target, AKT. Similar effects were observed by targeting ErbB3 with either siRNAs or the neutralizing ErbB3 monoclonal antibodies huHER3-8 and NG33. In addition, pertuzumab-mediated inhibition of ErbB2 …

Human Ips Cell-Derived Astrocyte Transplants Preserve Respiratory Function After Spinal Cord Injury., Ke Li, Elham Javed, Daniel Scura, Tamara J. Hala, Suneil Seetharam, Aditi Falnikar, Jean-Philippe Richard, Ashley Chorath, Nicholas J. Maragakis, Megan C. Wright, Angelo C. Lepore

Department of Neuroscience Faculty Papers

Transplantation-based replacement of lost and/or dysfunctional astrocytes is a promising therapy for spinal cord injury (SCI) that has not been extensively explored, despite the integral roles played by astrocytes in the central nervous system (CNS). Induced pluripotent stem (iPS) cells are a clinically-relevant source of pluripotent cells that both avoid ethical issues of embryonic stem cells and allow for homogeneous derivation of mature cell types in large quantities, potentially in an autologous fashion. Despite their promise, the iPS cell field is in its infancy with respect to evaluating in vivo graft integration and therapeutic efficacy in SCI models. Astrocytes express …

Muscle Weakness During Aging: A Deficiency State Involving Declining Angiogenesis, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

This essay begins by proposing that muscle weakness of old age from sarcopenia is due in large part to reduced capillary density in the muscles, as documented in 9 reports of aged persons and animals. Capillary density (CD) is determined by local levels of various angiogenic factors, which also decline in muscles with aging, as reported in 7 studies of old persons and animals. There are also numerous reports of reduced CD in the aged brain and other studies showing reduced CD in the kidney and heart of aged animals. Thus a waning angiogenesis throughout the body may be …

Rna-Seq Analysis Of Differential Splice Junction Usage And Intron Retentions By Dexseq, Yafang Li, Xiayu Rao, William W. Mattox, Christopher I. Amos, Bin Liu

Dartmouth Scholarship

Alternative splicing is an important biological process in the generation of multiple functional transcripts from the same genomic sequences. Differential analysis of splice junctions (SJs) and intron retentions (IRs) is helpful in the detection of alternative splicing events. In this study, we conducted differential analysis of SJs and IRs by use of DEXSeq, a Bioconductor package originally designed for differential exon usage analysis in RNA-seq data analysis. We set up an analysis pipeline including mapping of RNA-seq reads, the preparation of count tables of SJs and IRs as the input files, and the differential analysis in DEXSeq. We analyzed the …

Coordination Between Autophagy And The Heat Shock Response: Evidence From Exercise In Animals And Humans, Nathan H. Cole

Health, Exercise, and Sports Sciences ETDs

Proteins play a critical role in nearly every biological activity. In consequence, organismal health and homeostasis often hinges on the ability of intracellular regulatory systems to sustain the quality and function of these diverse, structurally complex macromolecules. Correct protein function depends on correct form, and during periods of destabilizing cellular stress, protein quality is managed in part by the heat shock response, which acts to support, isolate, and reform new or damaged proteins, and in part by the autophagic recycling of abnormal proteins, cytotoxic protein aggregates, and terminally damaged organelles. We conducted a pooled analysis of available research in humans …

Association Of Hyperchloremia With Hospital Mortality In Critically Ill Septic Patients, Javier A. Neyra, Fabrizio Canepa-Escaro, Xilong Li, John Manllo, Beverley Adams-Huet, Jerry Yee, Lenar Yessayan

Nephrology Articles

OBJECTIVES: Hyperchloremia is frequently observed in critically ill patients in the ICU. Our study aimed to examine the association of serum chloride (Cl) levels with hospital mortality in septic ICU patients.

DESIGN: Retrospective cohort study.

SETTING: Urban academic medical center ICU.

PATIENTS: ICU adult patients with severe sepsis or septic shock who had Cl measured on ICU admission were included. Those with baseline estimated glomerular filtration rate less than 15 mL/min/1.73 m or chronic dialysis were excluded.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Of 1,940 patients included in the study, 615 patients (31.7%) had hyperchloremia (Cl ≥ 110 mEq/L) on …

Pkcε Is An Essential Mediator Of Prostate Cancer Bone Metastasis., Alvaro Gutierrez-Uzquiza, Cynthia Lopez-Haber University Of Pennsylvania, Danielle L. Jernigan, Alessandro Fatatis, Marcelo G. Kazanietz

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

UNLABELLED: The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced …

Recurrent Streptococcus Equi Subsp. Zooepidemicus Bacteremia In An Infant, Joshua R. Watson, Amy Leber, Sridhar Velineni, John F. Timoney, Monica I. Ardura

Maxwell H. Gluck Equine Research Center Faculty Publications

We describe a case of an infant with recurrent bacteremia caused by Streptococcus equi subsp. zooepidemicus, likely transmitted from mother to infant. Our case highlights the importance of an epidemiological history and molecular diagnostics in ascertaining insights into transmission, pathogenesis, and optimal management.

Novel Human Abcc9/Sur2 Brain-Expressed Transcripts And An Eqtl Relevant To Hippocampal Sclerosis Of Aging, Peter T. Nelson, Wang-Xia Wang, Bernard R. Wilfred, Angela Wei, James Dimayuga, Qingwei Huang, Eseosa T. Ighodaro, Sergey C. Artiushin, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging. The main goals of this study were 1 > to detect the ABCC9 variants and define the specific 3′ untranslated region (3′UTR) for each variant in human brain, and 2 > to determine whether a polymorphism (rs704180) associated with risk for hippocampal sclerosis of aging pathology is also associated with variation in ABCC9 transcript expression and/or splicing. Rapid amplification of ABCC9 cDNA ends (3′RACE) provided evidence of novel 3′ UTR portions of ABCC9 in human brain. In silico and experimental studies were performed focusing on …

Human And Murine Ifit1 Proteins Do Not Restrict Infection Of Negative-Sense Rna Viruses Of The Orthomyxoviridae, Bunyaviridae, And Filoviridae Families, Amelia K. Pinto, Graham D. Williams, Kristy J. Szretter, James P. White, José Luiz Proença-Módena, Gai Liu, Judith Olejnik, James D. Brien, Hideki Ebihara, Elke Mühlberger, Gaya Amarasinghe, Michael S. Diamond, Adrianus C.M. Boon

Open Access Publications

UNLABELLED: Interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) is a host protein with reported cell-intrinsic antiviral activity against several RNA viruses. The proposed basis for the activity against negative-sense RNA viruses is the binding to exposed 5'-triphosphates (5'-ppp) on the genome of viral RNA. However, recent studies reported relatively low binding affinities of IFIT1 for 5'-ppp RNA, suggesting that IFIT1 may not interact efficiently with this moiety under physiological conditions. To evaluate the ability of IFIT1 to have an impact on negative-sense RNA viruses, we infected Ifit1(-/-) and wild-type control mice and primary cells with four negative-sense RNA viruses (influenza …

Staphylococcus Aureus Biofilms Induce Macrophage Dysfunction Through Leukocidin Ab And Alpha-Toxin., Tyler D. Scherr, Mark L. Hanke, Ouwen Huang, David B.A. James, Alexander R. Horswill, Kenneth W. Bayles, Paul D. Fey, Victor J. Torres, Tammy Kielian

Journal Articles: Pathology and Microbiology

UNLABELLED: The macrophage response to planktonic Staphylococcus aureus involves the induction of proinflammatory microbicidal activity. However, S. aureus biofilms can interfere with these responses in part by polarizing macrophages toward an anti-inflammatory profibrotic phenotype. Here we demonstrate that conditioned medium from mature S. aureus biofilms inhibited macrophage phagocytosis and induced cytotoxicity, suggesting the involvement of a secreted factor(s). Iterative testing found the active factor(s) to be proteinaceous and partially agr-dependent. Quantitative mass spectrometry identified alpha-toxin (Hla) and leukocidin AB (LukAB) as critical molecules secreted by S. aureus biofilms that inhibit murine macrophage phagocytosis and promote cytotoxicity. A role for Hla …

A Mitochondria-Anchored Isoform Of The Actin-Nucleating Spire Protein Regulates Mitochondrial Division, Uri Manor, Sadie Bartholomew, Gonen Golani, Eric Christenson, Michael Kozlov, Henry Higgs, James Spudich, Jennifer Lippincott-Schwartz

Dartmouth Scholarship

Mitochondrial division, essential for survival in mammals, is enhanced by an inter-organellar process involving ER tubules encircling and constricting mitochondria. The force for constriction is thought to involve actin polymerization by the ER-anchored isoform of the formin protein inverted formin 2 (INF2). Unknown is the mechanism triggering INF2-mediated actin polymerization at ER-mitochondria intersections. We show that a novel isoform of the formin-binding, actin-nucleating protein Spire, Spire1C, localizes to mitochondria and directly links mitochondria to the actin cytoskeleton and the ER. Spire1C binds INF2 and promotes actin assembly on mitochondrial surfaces. Disrupting either Spire1C actin- or formin-binding activities reduces mitochondrial constriction …

Familiar Face Detection In 180ms, Matteo Visconti Di Oleggio Castello, M. Ida Gobbini

Dartmouth Scholarship

The visual system is tuned for rapid detection of faces, with the fastest choice saccade to a face at 100ms. Familiar faces have a more robust representation than do unfamiliar faces, and are detected faster in the absence of awareness and with reduced attentional resources. Faces of family and close friends become familiar over a protracted period involving learning the unique visual appearance, including a view-invariant representation, as well as person knowledge. We investigated the effect of personal familiarity on the earliest stages of face processing by using a saccadic-choice task to measure how fast familiar face detection can happen. …

Atomic Structure Of Grk5 Reveals Distinct Structural Features Novel For G Protein-Coupled Receptor Kinases, Konstantin E. Komolov, Anshul Bhardwaj, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

G protein-coupled receptor kinases (GRKs) are members of the protein kinase A, G, and C families (AGC) and play a central role in mediating G protein-coupled receptor phosphorylation and desensitization. One member of the family, GRK5, has been implicated in several human pathologies, including heart failure, hypertension, cancer, diabetes, and Alzheimer disease. To gain mechanistic insight into GRK5 function, we determined a crystal structure of full-length human GRK5 at 1.8 Å resolution. GRK5 in complex with the ATP analog 5'-adenylyl β,γ-imidodiphosphate or the nucleoside sangivamycin crystallized as a monomer. The C-terminal tail (C-tail) of AGC kinase domains is a highly …

Hepatocyte Growth Factor And Met Support Mouse Enteric Nervous System Development, The Peristaltic Response, And Intestinal Epithelial Proliferation In Response To Injury, Marina Avetisyan, Hongtao Wang, Ellen Merrick Schill, Saya Bery, John R. Grider, John A. Hassell, Thaddeus Stappenbeck, Robert O. Heuckeroth

Open Access Publications

UNLABELLED: Factors providing trophic support to diverse enteric neuron subtypes remain poorly understood. We tested the hypothesis that hepatocyte growth factor (HGF) and the HGF receptor MET might support some types of enteric neurons. HGF and MET are expressed in fetal and adult enteric nervous system. In vitro, HGF increased enteric neuron differentiation and neurite length, but only if vanishingly small amounts (1 pg/ml) of glial cell line-derived neurotrophic factor were included in culture media. HGF effects were blocked by phosphatidylinositol-3 kinase inhibitor and by MET-blocking antibody. Both of these inhibitors and MEK inhibition reduced neurite length. In adult mice, …

Truncating Mutation In The Autophagy Gene Uvrag Confers Oncogenic Properties And Chemosensitivity In Colorectal Cancers, Shanshan He, Zhen Zhao, Yongfei Yang, Douglas O'Connell, Xiaowei Zhang, Soohwan Oh, Binyun Ma, Joo-Hyung Lee, Tian Zhang, Bino Varghese, Janae Yip, Sara Dolatshahi Pirooz, Ming Li, Yong Zhang, Guo-Min Li, Sue Ellen Martin, Keigo Machida, Chengyu Liang

Toxicology and Cancer Biology Faculty Publications

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumour suppressor, is mutated in common human cancers. Here we demonstrate that the cancer-related UVRAG frameshift (FS), which does not result in a null mutation, is expressed as a truncated UVRAG^FS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAG^FS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAG^FS can …