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The Rna Decapping Machinery Is A Conserved Anti-Bunyaviral Restriction Factor, Kaycie Christine Hopkins Jan 2013

The Rna Decapping Machinery Is A Conserved Anti-Bunyaviral Restriction Factor, Kaycie Christine Hopkins

Publicly Accessible Penn Dissertations

Arthropod-borne viruses (arboviruses) are an important class of emerging pathogens that cause mortality and morbidity worldwide. As obligate intracellular parasites with limited coding capacity, viruses must hijack host factors to replicate while evading host detection. To date, no specific therapeutic interventions exist for arboviruses and most lack FDA approved vaccines. This is in part due to a lack of understanding of viral-host interactions. To identify host factors that impact infection, we performed a genome-wide RNAi screen in Drosophila and identified 131 genes that affected infection of the mosquito-transmitted bunyavirus Rift Valley Fever virus (RVFV). Dcp2, the catalytic component of the ...


Connectable Components For Protein Design, Gabriel B. Gonzalez Jan 2013

Connectable Components For Protein Design, Gabriel B. Gonzalez

Publicly Accessible Penn Dissertations

Protein design requires reusable, trustworthy, and connectable parts in order to scale to complex challenges. The recent explosion of protein structures stored within the Protein Data Bank provides a wealth of small motifs we can harvest, but we still lack tools to combine them into larger proteins. Here I explore two approaches for connecting reusable protein components on two different length scales. On the atomic scale, I build an interactive search engine for connecting chemical fragments together. Protein fragments built using this search engine recapitulate native-like protein assemblies that can be integrated into existing protein scaffolds using backbone search engines ...


Distributed Activity Patterns For Objects And Their Features: Decoding Perceptual And Conceptual Object Processing In Information Networks Of The Human Brain, Marc N. Coutanche Jan 2013

Distributed Activity Patterns For Objects And Their Features: Decoding Perceptual And Conceptual Object Processing In Information Networks Of The Human Brain, Marc N. Coutanche

Publicly Accessible Penn Dissertations

How are object features and knowledge-fragments represented and bound together in the human brain? Distributed patterns of activity within brain regions can encode distinctions between perceptual and cognitive phenomena with impressive specificity. The research reported here investigated how the information within regions' multi-voxel patterns is combined in object-concept networks. Chapter 2 investigated how memory-driven activity patterns for an object's specific shape, color, and identity become active at different stages of the visual hierarchy. Brain activity patterns were recorded with functional magnetic resonance imaging (fMRI) as participants searched for specific fruits or vegetables within visual noise. During time-points in which ...


Redundant Neuromodulatory Mechanisms That Control Fear Memory Consolidation, Matthew Young Jan 2013

Redundant Neuromodulatory Mechanisms That Control Fear Memory Consolidation, Matthew Young

Publicly Accessible Penn Dissertations

The ability to reliably and powerfully store memories for frightening experiences is crucial to survival in an ever-changing and potentially dangerous environment. Consolidation is the process by which long-term memories are stored in the brain, and much is understood about the processes that occur within a neuron in the hours after a learning event that stabilize learning-induced changes. However, the specific mechanisms through which fear exacerbates those processes remains unclear. Neuromodulators are a prime object of research to understand the consolidation of fear memory given that their release is a hallmark of the fear response. While several neuromodulatory systems are ...


Regulation Of Egf Receptor Dynamics By Protein Tyrosine Phosphatases, Calixte Monast Jan 2013

Regulation Of Egf Receptor Dynamics By Protein Tyrosine Phosphatases, Calixte Monast

Publicly Accessible Penn Dissertations

The phosphorylated epidermal growth factor receptor (EGFR) initiates intracellular signaling processes that regulate cell growth, survival, and migration, and disregulated EGFR-mediated signaling occurs in many cancers. While the processes that lead to EGFR activation and phosphorylation have been studied in detail, quantitative aspects of the spatiotemporal regulation of EGFR by protein tyrosines phosphatases (PTPs) are not well understood. To begin to address this, we developed a new compartmentalized mechanistic model of EGFR phosphorylation dynamics and used it to interpret quantitative biochemical measurements to show that EGFR is dephosphorylated at the plasma membrane and in the cell interior with a time ...


Mechanical Development And Functional Mechanosensitivity During Early Cardiogenesis, Stephanie Feldman Majkut Jan 2013

Mechanical Development And Functional Mechanosensitivity During Early Cardiogenesis, Stephanie Feldman Majkut

Publicly Accessible Penn Dissertations

This thesis addresses the questions of when and how mechanical stiffness arises during embryonic heart development and how mechanics affects early cardiomyocyte and myocardium contractile function and cytoskeletal organization. Previous studies addressing how mechanics influence the contractile and electrochemical capacity of mature cardiomyocytes on compliant substrates are reviewed in light of theory explaining how contractile striated fibers might optimally align on intermediate substrates. Embryonic heart and brain tissue stiffness through early development are measured by micropipette aspiration, and the earliest functional heart is found to be three-fold stiffer than early embryonic tissue while brain remains soft. Contraction strain in intact ...


The Influence Of Cd4+ T Cell Affinity For Self-Antigen On The Development Of Inflammatory Arthritis, Olivia Alice Perng Jan 2013

The Influence Of Cd4+ T Cell Affinity For Self-Antigen On The Development Of Inflammatory Arthritis, Olivia Alice Perng

Publicly Accessible Penn Dissertations

CD4+ T cells make a crucial contribution to the development of inflammatory arthritis both in humans and in mouse models. However, how the affinity with which T cells recognize target antigens might shape disease development and influence treatment modalities is poorly understood. We have examined these phenomena in mouse models of autoimmune arthritis: TS1xHACII and TS1(SW)xHACII mice express influenza hemagglutinin (HA) as a neo-self peptide and co-express transgenic TCRs that have either high affinity (TS1xHACII) or low affinity (TS1(SW)xHACII) for the HA-derived MHCII determinant, S1. Despite extensive deletion of T cells bearing autoreactive TCRs, arthritis spontaneously ...


Impact Of Il-27 On Regulatory T Cell Responses, Aisling Catherine O'Hara Jan 2013

Impact Of Il-27 On Regulatory T Cell Responses, Aisling Catherine O'Hara

Publicly Accessible Penn Dissertations

Interleukin (IL)–27 is a heterodimeric cytokine with potent inhibitory properties. Thus, mice that lack IL–27–mediated signaling develop exaggerated inflammatory responses during toxoplasmosis as well as other infections or autoimmune processes. While regulatory T (Treg) cells are critical to limit inflammation, their role during toxoplasmosis is controversial because this infection results in a dramatic decrease in the total numbers of these cells associated with reduced levels of IL–2. Because IL–27 suppresses IL–2, we initially hypothesized that it was responsible for the Treg cell “crash”. Thus, we examined the role of IL–27 and IL–2 ...


Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera Jan 2013

Control Of The Tumor Suppressor P53 By Regulating Mdm2 Activity And Stability, Ruchira S. Ranaweera

Publicly Accessible Penn Dissertations

p53 is a tumor suppressor that is widely mutated or deleted in cancer cells. Mdm2, an E3 ubiquitin ligase, is the master regulator of p53. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. There are complex regulatory mechanisms balancing the activity and stability of Mdm2 in a cell. Mdm2 has an extremely short half-life in the unstressed cell and its regulation is not well understood. Like most E3 ligases, Mdm2 can autoubiquitinate. Previously, the sole function of autoubiquitination was thought to be to signal Mdm2 degradation. Here I show that ...


Risk Factors For And Impact Of Ambulatory Urinary Tract Infections Caused By High Mic-Fluoroquinolone Susceptible E. Coli In Women, Pinyo Rattanaumpawan Jan 2013

Risk Factors For And Impact Of Ambulatory Urinary Tract Infections Caused By High Mic-Fluoroquinolone Susceptible E. Coli In Women, Pinyo Rattanaumpawan

Publicly Accessible Penn Dissertations

Coincident with the increasing use of fluoroquinolones (FQs) as the first-line agent for treatment of urinary tract infections (UTIs) in adults, the prevalence of high MIC fluoroquinolone susceptible E. coli (high MIC-FQSEC) which are the E. coli isolates with reduced susceptibility to FQs has increased substantially. The high MIC-FQSEC strains may serve as an important reservoir for FQ resistance in that treatment of these organisms with a FQ has been associated with future emergence of resistance.

To establish an effective program for controlling emergence of FQ resistance, it is necessary to understand the risk factors for, and impact of infection ...


Methods In And Applications Of The Sequencing Of Short Non-Coding Rnas, Paul Ryvkin Jan 2013

Methods In And Applications Of The Sequencing Of Short Non-Coding Rnas, Paul Ryvkin

Publicly Accessible Penn Dissertations

Short non-coding RNAs are important for all domains of life. With the advent of modern molecular biology their applicability to medicine has become apparent in settings ranging from diagonistic biomarkers to therapeutics and fields ranging from oncology to neurology. In addition, a critical, recent technological development is high-throughput sequencing of nucleic acids. The convergence of modern biotechnology with developments in RNA biology presents opportunities in both basic research and medical settings. Here I present two novel methods for leveraging high-throughput sequencing in the study of short non-coding RNAs, as well as a study in which they are applied to Alzheimer ...


Stress, Monoamines, And Cognitive Flexibility, Kevin Snyder Jan 2013

Stress, Monoamines, And Cognitive Flexibility, Kevin Snyder

Publicly Accessible Penn Dissertations

Stress has been implicated in psychiatric disorders that are characterized by impaired executive function, which is mediated by the prefrontal cortex (PFC). The stress-related neuropeptide, corticotropin-releasing factor (CRF) regulates monoamine systems that project to the PFC, including the locus coeruleus norepinephrine (LC-NE) system and the dorsal raphe-serotonin (DRN-5-HT) system. CRF actions on these systems may underlie cognitive symptoms of stress-related disorders. The age at which stress occurs can determine its impact, and adolescent stress has been linked to adult psychopathology. This dissertation explores the role of CRF in stress-induced modulation of the LC-NE and DRN-5-HT systems and the developmental time ...


The Role Of The Hippocampus In Representations Of Emotional Memory, Melissa Eveline Wang Jan 2013

The Role Of The Hippocampus In Representations Of Emotional Memory, Melissa Eveline Wang

Publicly Accessible Penn Dissertations

Although the hippocampus has long been implicated in contextual fear learning, the exact function of this brain structure is unclear. It is generally thought to encode a spatial context with which a fear memory can be associated, but how it may accomplish this and whether it plays a role in emotional memory is largely unknown. It is also unclear whether the hippocampus acts as a single unitary structure, or whether the dorsal and ventral poles, which exhibit differential connectivity to other brain regions, function independently. This dissertation examines the involvement of the hippocampus in emotional learning. A contextual fear conditioning ...


Forkhead Transcription Factors Foxp1 And Foxp4 Regulate T Cell Development And Function, Karla Rose Wiehagen Jan 2013

Forkhead Transcription Factors Foxp1 And Foxp4 Regulate T Cell Development And Function, Karla Rose Wiehagen

Publicly Accessible Penn Dissertations

Transcription factors regulate T cell fates at every stage of development and differentiation. Members of the FoxP family of Forkhead transcription factors are essential for normal T lineage development; Foxp3 is required for regulatory T cell generation and function, and Foxp1 is necessary for the development of naïve T cells. FoxP family member Foxp4 is highly homologous to Foxp1 and has been shown to dimerize with other FoxP proteins.

In this thesis, we report the first studies of Foxp4 in T lymphocytes. Using a CD4Cre-mediated conditional knockout approach we evaluated the roles for Foxp4 regulation in the T lineage ...


Abnormal Smooth Muscle Contraction Alters Gut Motility And Propagates Epithelial Invasion In The Larval Zebrafish Intestine, Joshua Abrams Jan 2013

Abnormal Smooth Muscle Contraction Alters Gut Motility And Propagates Epithelial Invasion In The Larval Zebrafish Intestine, Joshua Abrams

Publicly Accessible Penn Dissertations

Coordinated smooth muscle contraction is critical for force production and proper functioning of numerous organ systems. Activation at the myosin motor domain via phosphorylated myosin light chain (phospho-MLC) remains the primary signal to initiate contraction, but it is now appreciated that there are additional force modulators also present in smooth muscle. One particularly well studied modulatory protein is Caldesmon (CaD), which has been implicated in controlling contractile force in vascular smooth muscle, however little is known of CaD's physiological role in vivo. Studies in vitro have shown that CaD inhibits actomyosin interactions and that this effect is reversed after ...


The Neural Representation Of Value And Individual Differences In Human Intertemporal Choice, Nicole Cooper Jan 2013

The Neural Representation Of Value And Individual Differences In Human Intertemporal Choice, Nicole Cooper

Publicly Accessible Penn Dissertations

Intertemporal choices, or decisions that involve tradeoffs between rewards and time, are ubiquitous in our daily lives. The tendency to devalue, or discount, future rewards has been linked to maladaptive long-term health and financial outcomes. Despite their broad clinical relevance, individual differences in discounting preferences are poorly understood. In this thesis, we make progress on the understanding of the neural basis of these decisions and factors that affect individual differences. The first two chapters focus on neurobiology. Chapter 2 investigates the decision-related variables that best explain the observed patterns of BOLD activity in ventromedial prefrontal cortex (VMPFC) and ventral striatum ...


Jip1 Regulates Axonal Transport Of App And Autophagosomes Via Coordination Of Kinesin And Dynein Motors, Meng-Meng Fu Jan 2013

Jip1 Regulates Axonal Transport Of App And Autophagosomes Via Coordination Of Kinesin And Dynein Motors, Meng-Meng Fu

Publicly Accessible Penn Dissertations

Neurons are specialized cells that extend polarized processes called dendrites and axons in order to maintain synaptic connections over long distances. Consequently, neuronal homeostasis requires axonal transport of organelles, such as mitochondria, synaptic vesicles, and autophagosomes. The microtubule-based motors responsible for long-distance fast axonal transport are the anterograde kinesin motors and the retrograde dynein motors. Two cargos that exhibit robust axonal transport characterized by high speeds with few directional switches are APP- (amyloid precursor protein) positive vesicles and autophagosomes. While APP-positive vesicles transport occurs in both anterograde and retrograde directions, autophagosomes move unidirectionally in the retrograde direction. Here, we demonstrate ...


Neurodegeneration After Cardiac Arrest: Cell Death Mechanisms And Methods Of Neuroprotection, Michael Paine Jan 2013

Neurodegeneration After Cardiac Arrest: Cell Death Mechanisms And Methods Of Neuroprotection, Michael Paine

Publicly Accessible Penn Dissertations

Brain injury after cardiac arrest is a significant contributor to morbidity and mortality. Selectively vulnerable neuron populations undergo delayed neurodegeneration in the hours to days following reperfusion. Multiple factors influence neuronal death after global brain ischemia, including excitatory synaptic input, mitochondrial dysfunction, oxidative stress, inflammation, and disruption of intracellular Ca2+ homeostasis. In hippocampal CA1 pyramidal neurons, these factors activate cell death via pathologic activity of calpains, the family of Ca2+-dependent proteases, and calpain inhibition protects against neurodegeneration. Therefore, we hypothesized that pathologic calpain activity is necessary and sufficient for neurodegeneration in other selectively vulnerable neuron populations. In this thesis ...


Phenotypic Characteristics Of Mucosally Transmitted Hiv-1, Nicholas F. Parrish Jan 2013

Phenotypic Characteristics Of Mucosally Transmitted Hiv-1, Nicholas F. Parrish

Publicly Accessible Penn Dissertations

Mucosal transmission accounts for the majority of new human immunodeficiency virus type 1 (HIV-1) infections and results in a genetically and phenotypically homogenous founder virus population in 60-80 percent of cases. Biological properties common to these transmitted and founder (T/F) viruses but not chronic control (CC) viruses would define key targets for microbicides and vaccines. To identify such properties, we tested 45 T/F and 52 CC envelope glycoproteins (Envs) from the best studied and most prevalent HIV-1 subtypes (B and C, respectively) in various pseudotype assays to determine their receptor and coreceptor interaction, tropism for primary CD4+ T ...


The Interplay Between Lewy Body-Like Alpha-Synuclein Aggregates Nd Protein Degradation Pathways In Cell-Based Model Of Parkinson's Disease, Selcuk Aski Tanik Jan 2013

The Interplay Between Lewy Body-Like Alpha-Synuclein Aggregates Nd Protein Degradation Pathways In Cell-Based Model Of Parkinson's Disease, Selcuk Aski Tanik

Publicly Accessible Penn Dissertations

Cytoplasmic alpha-synuclein (a-syn) aggregates, including Lewy bodies (LBs), are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson's disease (PD). Activation of intracellular protein degradation pathways (Pdps) to eliminate these aggregates has been proposed as a therapeutic approach for PD and other synucleinopathies, but the interplay between LB-like a-syn aggregates and Pdps is not completely understood. Here, we investigate this interplay by utilizing a recently developed cellular model in which intracellular LB-like a-syn inclusions accumulate after delivery of pre-formed a-syn fibrils (Pffs) into a-syn-expressing HEK293 cells or cultured primary neurons. This thesis describes the interplay between LB-like ...


Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe Jan 2013

Change And Impact Of Microrna Modification With Age In Drosophila Melanogaster, Masashi Abe

Publicly Accessible Penn Dissertations

microRNAs (miRNAs) are 20~24nt small RNAs that are critical for many biological aspects, from development to age-associated processes. Starting from the identification of the first miRNA, lin-4, hundreds of miRNAs have been discovered across species. To reveal the role of miRNAs in aging, studies have profiled changes in miRNA levels with age. However, increasing evidence suggests that miRNAs show heterogeneity in length and sequence in different biological contexts. Despite the observation of such heterogeneity, it is largely unknown how such heterogeneity is generated, and whether it is biologically regulated or important. Here we report the characterization of a novel ...


Evasion Of Host Recognition By Phase Variation In Haemophilus Influenzae, Sarah Clark Jan 2013

Evasion Of Host Recognition By Phase Variation In Haemophilus Influenzae, Sarah Clark

Publicly Accessible Penn Dissertations

Haemophilus influenzae colonizes the human respiratory tract, and is a major source of disease. Antibody and complement contribute to the limitation of H. influenzae colonization. This work explores bacterial factors that aid in the evasion of antibody recognition and subsequent complement-mediated lysis. Antibody recognition of H. influenzae is affected by the phase variation of lipopolysaccharide (LPS) structures. Phase variation refers to the stochastic, high frequency on/off switching in gene expression. One phase variable gene, lic1A, controls the attachment of the small molecule phosphorylcholine (ChoP) to the LPS. We found that ChoP-expressing bacteria had reduced antibody binding and increased survival ...


Epigenomic And Transcriptional Regulation Of Hepatic Metabolism By Rev-Erb And Hdac3, Dan Feng Jan 2013

Epigenomic And Transcriptional Regulation Of Hepatic Metabolism By Rev-Erb And Hdac3, Dan Feng

Publicly Accessible Penn Dissertations

Metabolic activities are regulated by the circadian clock, and disruption of the clock exacerbates metabolic diseases including obesity and diabetes. Transcriptomic studies in metabolic organs suggested that the circadian clock drives the circadian expression of important metabolic genes. Here we show that histone deacetylase 3 (HDAC3) is recruited to the mouse liver genome in a circadian manner. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Diurnal recruitment of HDAC3 corresponds to the expression pattern of REV-ERBα, an important component of the circadian clock. REV-ERBα colocalizes with HDAC3 near genes regulating lipid ...


Using Model Proteins To Study Tyrosine Oxidation-Reduction: Reversible Voltammograms, Long-Lived Radicals And Detailed Design Of The Radical Site, Melissa C. Martínez-Rivera Jan 2013

Using Model Proteins To Study Tyrosine Oxidation-Reduction: Reversible Voltammograms, Long-Lived Radicals And Detailed Design Of The Radical Site, Melissa C. Martínez-Rivera

Publicly Accessible Penn Dissertations

Amino acid radicals have been found as key components in a number of biological redox processes. In specific, redox−active tyrosine residues play an essential role in DNA biosynthesis and photosynthesis, among other processes. The thermodynamic and kinetic properties of one−electron redox reactions involving tyrosine have long been obscured by the highly unstable nature of the products of tyrosine oxidation. Remarkable control of these species is achieved within natural proteins. Proteins must, therefore, provide interactions to the amino acid cofactor to generate, control and direct the redox chemistry within the protein milieu. Electrochemical characterization of redox−active tyrosine residues ...


Adaptation Of The Retina To Stimulus Correlations, Kristina D. Simmons Jan 2013

Adaptation Of The Retina To Stimulus Correlations, Kristina D. Simmons

Publicly Accessible Penn Dissertations

Visual scenes in the natural world are highly correlated. To efficiently encode such an environment with a limited dynamic range, the retina ought to reduce correlations to maximize information. On the other hand, some redundancy is needed to combat the effects of noise. Here we ask how the degree of redundancy in retinal output depends on the stimulus ensemble. We find that retinal output preserves correlations in a spatially correlated stimulus but adaptively reduces changes in spatio-temporal input correlations. The latter effect can be explained by stimulus-dependent changes in receptive fields. We also find evidence that horizontal cells in the ...


Defining A Regulatory Role For The Hsv Glycoprotein B Membrane Proximal Region In Membrane Association, Spencer Shelly Jan 2013

Defining A Regulatory Role For The Hsv Glycoprotein B Membrane Proximal Region In Membrane Association, Spencer Shelly

Publicly Accessible Penn Dissertations

Herpes simplex virus (HSV) entry requires four essential glycoproteins (gD, gH/gL, and gB) to enable fusion between the virion envelope and the cellular membrane. The fusion cascade is activated by gD binding to one of its receptors, nectin-1 or HVEM. Glycoprotein B (gB), a class III viral fusion protein, mediates the fusion reaction, while data indicates that gH/gL acts as a regulator of gB. gB is trimeric and has a 773 amino acid ectodomain with a highly hydrophobic membrane proximal region (MPR) (residues 731-773) and two fusion loops (FL) per protomer. The post-fusion structure of gB was solved ...


Pathogenesis Of Neurodegenerative Diseases Via Templated Recruitment, Jing Guo Jan 2013

Pathogenesis Of Neurodegenerative Diseases Via Templated Recruitment, Jing Guo

Publicly Accessible Penn Dissertations

A common feature of many neurodegenerative diseases is the deposition of filamentous protein aggregates in the central nervous system (CNS), including neurofibrillary tangles (NFTs) composed of tau, and Lewy bodies (LBs) consisting of α-synuclein (α-syn), which are the hallmark lesions of Alzheimer's disease (AD) and Parkinson's disease (PD) respectively. What causes the conversion of normally soluble proteins into insoluble fibrils has always been enigmatic, and cell models that recapitulate the abnormal accumulation of tau into NFT-like aggregates were lacking due to high solubility of tau. Enlightened by in vitro studies showing nucleation-dependent fibrillization of tau, we tested the ...


Lipid And Protein Organizations In Model Membrane Systems- Membrane Curvature, Lipid Structure, Domain Formation, And Membrane Binding Kinetics, Wan-Ting Hsieh Jan 2013

Lipid And Protein Organizations In Model Membrane Systems- Membrane Curvature, Lipid Structure, Domain Formation, And Membrane Binding Kinetics, Wan-Ting Hsieh

Publicly Accessible Penn Dissertations

The composition and morphology of cellular membranes are highly dynamic. Potential parameters modulating protein and lipid distributions in different organelles include membrane shapes and the structures of lipids and proteins. Moreover, the concept of "lipid rafts" provides a prevailing view where nanodomains serve as centers for signal transduction, membrane trafficking, and cytoskeletal organization. In this contribution, we first investigated the lipid and protein organizations as a function of membrane curvature. To this end, a system consisting of solid-supported wavy membranes that exhibits a continuous curvature distribution with positive and negative curvature ranges was fabricated. Spatial distributions of ENTH (epsin N-terminal ...


The Role Of Tipe2 In The Regulation Of Inflammation And Tumorigenesis, Derek Johnson Jan 2013

The Role Of Tipe2 In The Regulation Of Inflammation And Tumorigenesis, Derek Johnson

Publicly Accessible Penn Dissertations

TIPE2 is a recently discovered regulator of immunity and inflammation. Here we describe a new function of TIPE2 in the regulation of Ras signaling and Tumorigenesis. By using various stimuli and inhibitors in T Cells and macrophages we discovered that TIPE2 is regulated at both the message and protein level by inflammatory stimuli. TIPE2 mRNA is regulated in the short to intermediate term by an NF-Kappa B induced micro RNA, and TIPE2 is also ubiquitylated and degraded, possibly by SCF-Beta TRCP. Mechanistically TIPE2 interacts with and inhibits the Ras-interacting domain of the RalGDS family of Ras effectors, leading to a ...


The Molecular Basis For Amino-Terminal Acetylation By Nat Proteins, Glen Liszczak Jan 2013

The Molecular Basis For Amino-Terminal Acetylation By Nat Proteins, Glen Liszczak

Publicly Accessible Penn Dissertations

Amino-terminal acetylation is a co-translational process that occurs on a majority of all eukaryotic proteins. This modification mediates a wide range of biological processes including but not limited to cellular apoptosis, enzyme regulation, protein localization and the N-end rule for protein degradation. The amino-terminal acetyltransferase (NAT) enzymes that catalyze this reaction are distinguished from one another on the basis of substrate specificity, which is dictated by the identity of the amino-terminal sequence of the substrate protein. The NatA complex harbors the greatest diversity for substrate selection and is responsible for acetylating a majority of all proteins that undergo this modification ...