Medical Biochemistry Commons^™

Tp53-Inducible Glycolysis And Apoptosis Regulator (Tigar) Metabolically Reprograms Carcinoma And Stromal Cells In Breast Cancer., Ying-Hui Ko, Marina Domingo-Vidal, Megan Roche, Zhao Lin, Diana Whitaker-Menezes, Erin Seifert, Claudia Capparelli, Madalina Tuluc, Ruth C. Birbe, Patrick Tassone, Joseph M. Curry, Àurea Navarro-Sabaté, Anna Manzano, Ramon Bartrons, Jaime Caro, Ubaldo E. Martinez-Outshoorn

Department of Medical Oncology Faculty Papers

A subgroup of breast cancers has several metabolic compartments. The mechanisms by which metabolic compartmentalization develop in tumors are poorly characterized. TP53 inducible glycolysis and apoptosis regulator (TIGAR) is a bisphosphatase that reduces glycolysis and is highly expressed in carcinoma cells in the majority of human breast cancers. Hence we set out to determine the effects of TIGAR expression on breast carcinoma and fibroblast glycolytic phenotype and tumor growth. The overexpression of this bisphosphatase in carcinoma cells induces expression of enzymes and transporters involved in the catabolism of lactate and glutamine. Carcinoma cells overexpressing TIGAR have higher oxygen consumption rates …

Natural And Induced Mitochondrial Phosphate Carrier Loss: Differential Dependence Of Mitochondrial Metabolism And Dynamics And Cell Survival On The Extent Of Depletion., Erin L. Seifert, Aniko Gál, Michelle G. Acoba, Qipei Li, Lauren Anderson-Pullinger, Tünde Golenár, Cynthia Moffat, Neal Sondheimer, Steven M. Claypool, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The relevance of mitochondrial phosphate carrier (PiC), encoded by SLC25A3, in bioenergetics is well accepted. However, little is known about the mechanisms mediating the cellular impairments induced by pathological SLC25A3 variants. To this end, we investigated the pathogenicity of a novel compound heterozygous mutation in SLC25A3 First, each variant was modeled in yeast, revealing that substituting GSSAS for QIP within the fifth matrix loop is incompatible with survival on non-fermentable substrate, whereas the L200W variant is functionally neutral. Next, using skin fibroblasts from an individual expressing these variants and HeLa cells with varying degrees of PiC depletion, PiC loss of …

The Yersinia Pestis Effector Yopm Inhibits Pyrin Inflammasome Activation., Dmitry Ratner, M Pontus A Orning, Megan K. Proulx, Donghai Wang, Mikhail A. Gavrilin, Mark D. Wewers, Emad S. Alnemri, Peter F. Johnson, Bettina Lee, Joan Mecsas, Nobuhiko Kayagaki, Jon D. Goguen, Egil Lien

Department of Biochemistry and Molecular Biology Faculty Papers

Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1β and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced …

Environmental Signaling Through The Target Of Rapamycin Complex 1 (Torc1) And The Regulation Of Epigenetic Mechanisms, Jason J. Workman

Theses and Dissertations (ETD)

The gene expression profile of a eukaryotic cell is responsive to a variety of extracellular stimuli, including nutrient availability, which allows cells to toggle between anabolism and catabolism based on the favorability of their environment. Much of this information is relayed through signaling complexes, such as the target of rapamycin complex 1 (TORC1), to downstream chromatin modifying enzymes. These enzymes impact the gene regulatory process through altered histone post-translation modifications, changes in chromatin structure, and docking of chromatin regulatory complexes. Yet, despite preliminary studies suggesting that TORC1 affects epigenetic mechanisms, including histone H3 lysine 56 acetylation (H3K56ac), almost nothing is …

Regulation Of Cancer Metastasis By Protein Kinase D1: A Global Regulatory Cascade, Aditya Ganju

Theses and Dissertations (ETD)

Protein Kinase D1 (PKD1) is a serine threonine kinase which is downregulated in Prostate, Breast and Colon Cancer. It functions as a tumor suppressor in different cancer cells. Downregulation of PKD1 is known to be associated with aggressiveness of the cancer. PKD1 is known to regulate many key oncogenic signaling pathways such as E-cadherin, β-catenin and Androgen Receptor signaling pathways. Aberrant expression of these oncogenic pathways leads to transformation of cells from normal to malignant phenotype, thereby leading to increased proliferation, growth and metastasis to distant organs of these cancer cells. Literature evidence also points to the fact that E-cadherin …

Palmitoylation Of Desmoglein 2 Is A Regulator Of Assembly Dynamics And Protein Turnover., Brett J. Roberts, Robert A. Svoboda, Andrew M. Overmiller, Joshua D. Lewis, Andrew P. Kowalczyk, My G. Mahoney, Keith R. Johnson, James K. Wahl

Department of Dermatology and Cutaneous Biology Faculty Papers

Desmosomes are prominent adhesive junctions present between many epithelial cells as well as cardiomyocytes. The mechanisms controlling desmosome assembly and remodeling in epithelial and cardiac tissue are poorly understood. We recently identified protein palmitoylation as a mechanism regulating desmosome dynamics. In this study, we have focused on the palmitoylation of the desmosomal cadherin desmoglein-2 (Dsg2) and characterized the role that palmitoylation of Dsg2 plays in its localization and stability in cultured cells. We identified two cysteine residues in the juxtamembrane (intracellular anchor) domain of Dsg2 that, when mutated, eliminate its palmitoylation. These cysteine residues are conserved in all four desmoglein …

Epoxyeicosatrienoic Acids Regulate Adipocyte Differentiation Of Mouse 3t3 Cells, Via Pgc-1Α Activation, Which Is Required For Ho-1 Expression And Increased Mitochondrial Function, Maayan Waldman, Lars Bellner, Luca Vanella, Joseph Schragenheim, Komal Sodhi, Shailendra P. Singh, Daohong Lin, Anand Lakhkar, Jiangwei Li, Edith Hochhauser, Michael Arad, Zbigniew Darzynkiewicz, Attallah Kappas, Nader G. Abraham

Biochemistry and Microbiology

Epoxyeicosatrienoic acid (EET) contributes to browning of white adipose stem cells to ameliorate obesity/diabetes and insulin resistance. In the current study, we show that EET altered preadipocyte function, enhanced peroxisome proliferation-activated receptor γ coactivator α (PGC-1α) expression, and increased mitochondrial function in the 3T3-L1 preadipocyte subjected to adipogenesis. Cells treated with EET resulted in an increase, P < 0.05, in PGC-1α and a decrease in mitochondria-derived ROS (MitoSox), P < 0.05. The EET increase in heme oxygenase-1 (HO-1) levels is dependent on activation of PGC-1α as cells deficient in PGC-1α (PGC-1α knockout adipocyte cell) have an impaired ability to express HO-1, P < 0.02. Additionally, adipocytes treated with EET exhibited an increase in mitochondrial superoxide dismutase (SOD) in a PGC-1α-dependent manner, P < 0.05. The increase in PGC-1α was associated with an increase in β-catenin, P < 0.05, adiponectin expression, P < 0.05, and lipid accumulation, P < 0.02. EET decreased heme levels and mitochondria-derived ROS (MitoSox), P < 0.05, compared to adipocytes that were untreated. EET also decreased mesoderm-specific transcript (MEST) mRNA and protein levels (P < 0.05). Adipocyte secretion of EET act in an autocrine/paracrine manner to increase PGC-1α is required for activation of HO-1 expression. This is the first study to dissect the mechanism by which the antiadipogenic and anti-inflammatory lipid, EET, induces the PGC-1α signaling cascade and reprograms the adipocyte phenotype by regulating mitochondrial function and HO-1 expression, leading to an increase in healthy, that is, small, adipocytes and a decrease in adipocyte enlargement and terminal differentiation. This is manifested by an increase in mitochondrial function and an increase in the canonical Wnt signaling cascade during adipocyte proliferation and terminal differentiation.

Changing Diagnostic Methods And Increased Detection Of Verotoxigenic Escherichia Coli, Ireland, Thomas Rice, Noreen Quinn, Roy D. Sleator, Brigid Lucey

Department of Biological Sciences Publications

The recent paradigm shift in infectious disease diagnosis from culture-based to molecular-based approaches is exemplified in the findings of a national study assessing the detection of verotoxigenic Escherichia coli infections in Ireland. The methodologic changes have been accompanied by a dramatic increase in detections of non-O157 verotoxigenic E. coli serotypes.

Peroxiredoxin Catalysis At Atomic Resolution, Arden Perkins, Derek Parsonage, Kimberly J. Nelson, O. Maduka Ogba, Paul Ha-Yeon Cheong, Leslie B. Poole, P. Andrew Karplus

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Peroxiredoxins (Prxs) are ubiquitous cysteine-based peroxidases that guard cells against oxidative damage, are virulence factors for pathogens, and are involved in eukaryotic redox regulatory pathways. We have analyzed catalytically active crystals to capture atomic resolution snapshots of a PrxQ-subfamily enzyme (from Xanthomonas campestris) proceeding through thiolate, sulfenate, and sulfinate species. These analyses provide structures of unprecedented accuracy for seeding theoretical studies, and show novel conformational intermediates giving insight into the reaction pathway. Based on a highly non-standard geometry seen for the sulfenate intermediate, we infer that the sulfenate formation itself can strongly promote local unfolding of the active site to …

Ehd1 As A Positive Regulator Of Macrophage Colony-Stimulating Factor-1 Receptor, Luke R. Cypher

Theses & Dissertations

The master regulator of the macrophage development, differentiation, proliferation, survival, phagocytosis, cytokine secretion, motility, adhesion, migration, and spreading is the receptor tyrosine kinase (RTK) colony stimulating factor-1 receptor (CSF-1R). Aberrant CSF-1R signaling is present amongst a variety of highly prevalent and devastating human diseases in the United States such as atherosclerosis, cancer, inflammatory bowel disease, arthritis, and neuro-demyelination/neuro-degeneration. A better understanding of basic mechanisms that govern macrophage development and function is of vital importance in treating patients afflicted with these conditions/diseases. CSF-1R presentation on the macrophage cell surface is a required precursor for CSF1- induced RTK dimerization (activation) and downstream …

Rnai Nanotechnology: A Platform For Sirna Screening And Cancer Gene Therapy, Mayurbhai Ravikant Patel

Seton Hall University Dissertations and Theses (ETDs)

Over the past two decades, advances in RNA structural biology have improved our understanding of the structures and folding properties of naturally occurring RNAs. RNA sequences and structures participate in many specific biological functions, such as those performed by messenger RNA (mRNA), ribosomal RNA (rRNA), transfer RNA (tRNA), micro RNA (miRNA), short-interfering RNA (siRNA), small nuclear RNA (snRNA) and many others. The noncoding RNAs, such as siRNA, do not express proteins but have been utilized in a wide range of applications, including RNA interference (RNAi) and the regulation of mRNA expression. These important biological functions have been implemented in gene …

Glucan Phosphatase Variants For Starch Phosphorylation, Matthew S. Gentry, Craig Vander Kooi

Molecular and Cellular Biochemistry Faculty Patents

Glucan phosphatase nucleotide or polypeptide variants of the presently-disclosed subject matter can alter the biophysical properties of starch in vitro or in planta, as well as the total starch biomass production in planta as compared to plants expressing wild-type glucan phosphatases. Plants producing the polypeptide variants of the presently-disclosed subject matter can have increased starch accumulation, increased starched biomass, and/or starch having desired biophysical properties. A method of the presently-disclosed subject matter for producing altered starch includes providing a plant that produces a glucan phosphatase polypeptide variant that comprises an amino acid mutation and collecting starch from the plant.

Inhibiting Androgen Receptor Nuclear Entry In Castration-Resistant Prostate Cancer, Julie A. Pollock, Suzanne E. Wardell, Alexander A. Parent, David B. Stagg, Stephanie J. Ellison, Holly M. Alley, Christina A. Chao, Scott A. Lawrence, James P. Stice, Ivan Spasojevic, Jennifer G. Baker, Sung Hoon Kim, Donald P. Mcdonnell, John A. Katzenellenbogen, John D. Norris

Chemistry Faculty Publications

Clinical resistance to the second-generation antiandrogen enzalutamide in castration resistant prostate cancer (CRPC), despite persistent androgen receptor (AR) activity in tumors, highlights the unmet medical need for next generation antagonists. We have identified and characterized tetra-aryl cyclobutanes (CBs) as a new class of competitive AR antagonists that exhibit a unique mechanism of action. These CBs are structurally distinct from current antiandrogens (hydroxyflutamide, bicalutamide, and enzalutamide), and inhibit AR-mediated gene expression, cell proliferation, and tumor growth in several models of CRPC. Conformational profiling revealed that CBs stabilize an AR conformation resembling an unliganded receptor. Using a variety of techniques, it was …

Surveillance, Epidemiological, And Virological Detection Of Highly Pathogenic H5n1 Avian Influenza Viruses In Duck And Poultry From Bangladesh, Wahedul Karim Ansari, Md Safiullah Parvej, Mohamed E. El Zowalaty, Sally Jackson, Stephen A. Bustin, Adel K. Ibrahim, Md Tanvir Rahman, Han Zhang, Mohammad Ferdousur Rahman Khan, Md Mostakin Ahamd, Md. Fasiur Rahman, Marzia Rahman, Khm Nazmul H. Nazir, Sultan Ahmed, Md Liakot Hossenn, Md Abdul Kafi, Mat Yamage, Nitish C. Debnath, Graba Ahmed, Hossam Ashour, Md Masoud, Ayman Noreddin, Md B. Rahman

Pharmacy Faculty Articles and Research

Avian influenza viruses (AIVs) continue to pose a global threat. Waterfowl are the main reservoir and are responsible for the spillover of AIVs to other hosts. This study was conducted as part of routine surveillance activities in Bangladesh and it reports on the serological and molecular detection of H5N1 AIV subtype. A total of 2169 cloacal and 2191 oropharyngeal swabs as well as 1725 sera samples were collected from live birds including duck and chicken in different locations in Bangladesh between the years of 2013 and 2014. Samples were tested using virus isolation, serological tests and molecular methods of RT-PCR. …

The Discovery Of A Novel, Ras-Mediated Nore1a/Pmliv Tumor Suppressor Complex., Jessica Mezzanotte Sharpe

Electronic Theses and Dissertations

Ras is the most commonly activated oncogene in human cancer. Activated Ras drives cell growth and proliferation by activating multiple mitogenic signaling pathways. However, Ras also has the paradoxical ability to promote anti-growth, pro-apoptotic, and pro-senescent signaling. The signaling pathways of many of these biological effectors remain poorly defined. One group of proteins capable of promoting Ras-induced apoptosis and cell cycle arrest is the RASSF family of tumor suppressors. Novel Ras Effector 1A, or NORE1A, was the first member of this family discovered and is a bona fide tumor suppressor that is lost or inactivated in a number of different …

Loss Of Exogenous Androgen Dependence By Prostate Tumor Cells Is Associated With Elevated Glucuronidation Potential, Brenna M. Zimmer, Michelle E. Howell, Qin Wei, Linlin Ma, Trevor Romsdahl, Eileen G. Loughman, Jennifer E. Markham, Javier Seravalli, Joseph J. Barycki, Melanie A. Simpson

Department of Biochemistry: Faculty Publications

Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD⁺-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate, and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen dependent versus castration resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration resistant tumor cells expressed higher …

Incidence Of Hypomagnesemia On Proton Pump Inhibitors At The Huntington Veterans Affairs Medical Center – Ihop, Ebrahim Sabbagh, Do, Chelsey R. Houchins, James Allman, Ii, Pharmd, Samson Teka, Md

Marshall Journal of Medicine

Abstract

Title: Incidence of hypomagnesemia on proton pump inhibitors at the Huntington Veterans Affairs Medical Center – IHOP

Purpose:

Proton pump inhibitors (PPIs), both prescription and over-the-counter, are widely used for the treatment of acid-related disease states such as dyspepsia, gastroesophageal reflex disease, esophagitis, and peptic ulcers. These medications are generally considered safe in most patient populations; however, there are several adverse effects that may occur with long-term use. Hypomagnesemia is a newer complication arising in the literature following multiple case reports over the past several years, although the true incidence of hypomagnesemia associated with PPI use remains unclear at …

The Α-Arrestin Arrdc3 Regulates The Endosomal Residence Time And Intracellular Signaling Of The Β2-Adrenergic Receptor., Xufan Tian, Roshanak Irannejad, Shanna L. Bowman, Yang Du, Manojkumar A. Puthenveedu, Mark Von Zastrow, Jeffrey L. Benovic

Department of Biochemistry and Molecular Biology Faculty Papers

Arrestin domain-containing protein 3 (ARRDC3) is a member of the mammalian α-arrestin family, which is predicted to share similar tertiary structure with visual-/β-arrestins and also contains C-terminal PPXY motifs that mediate interaction with E3 ubiquitin ligases. Recently, ARRDC3 has been proposed to play a role in regulating the trafficking of G protein-coupled receptors, although mechanistic insight into this process is lacking. Here, we focused on characterizing the role of ARRDC3 in regulating the trafficking of the β2-adrenergic receptor (β2AR). We find that ARRDC3 primarily localizes to EEA1-positive early endosomes and directly interacts with the β2AR in a ligand-independent manner. Although …

Gene Delivery Using Calcium Phosphate Nanoparticles: Optimization Of The Transfection Process And The Effects Of Citrate And Poly(L-Lysine) As Additives, Mohammed A. Khan, Victoria M. Wu, Shreya Ghosh, Vuk Uskoković

Pharmacy Faculty Articles and Research

Despite the long history of nanoparticulate calcium phosphate (CaP) as a non-viral transfection agent, there has been limited success in attempts to optimize its properties for transfection comparable in efficiency to that of viral vectors. Here we focus on the optimization of: (a) CaP nanoparticle precipitation conditions, predominantly supersaturation and Ca/P molar ratios; (b) transfection conditions, mainly the concentrations of the carrier and plasmid DNA; (c) the presence of surface additives, including citrate anion and cationic poly(l-lysine) (PLL). CaP nanoparticles significantly improved transfection with plasmid DNA encoding enhanced green fluorescent protein (eGFP) in pre-osteoblastic MC3T3-E1 cells compared to a commercial …

Mechanism Of Chimeric Vaccine Mediated Immune Suppression Of Human Dendritic Cells, Jacques Christian Mbongue

Loma Linda University Electronic Theses, Dissertations & Projects

Type 1 diabetes mellitus is a chronic inflammatory disease in which insulin producing β-cells of the pancreatic islets are killed by autoreactive cells of the immune system in response to a loss of tolerance. Dendritic cells (DC) interact predominantly with naïve T cells to regulate the delicate balance between immunity and tolerance required to maintain immunological homeostasis. In this dissertation, immature human dendritic cells (iDC) were inoculated with a chimeric fusion protein vaccine containing the pancreatic β-cell auto-antigen proinsulin linked to a mucosal adjuvant the cholera toxin B subunit (CTB-INS). Proteomic analysis of vaccine inoculated DCs revealed strong up-regulation of …

Role Of Protein Kinase G In Regulating Vascular Tone In Hypoxic Ovine Cerebral Arteries, Richard Burdette Thorpe

Loma Linda University Electronic Theses, Dissertations & Projects

Nitric oxide (NO) and its precursors have been used clinically to induce vasorelaxation long before the specific mechanism of how this operates was understood. With the discovery in 1977 of the influence of NO on guanylate cyclase, and the subsequent elucidation of the NO pathway, the role of cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) has been shown to be the main mediator of NO-induced vasorelaxation. Less well understood is the behavior of this pathway in conditions of long term hypoxia (LTH). It was later shown that LTH attenuates the ability of PKG to mediate vasorelaxation. How this operates is …

Molecular Basis And Consequences Of The Cytochrome C-Trna Interaction., Cuiping Liu, Aaron J Stonestrom, Thomas Christian, Jeongsik Yong, Ryuichi Takase, Ya-Ming Hou, Xiaolu Yang

Department of Biochemistry and Molecular Biology Faculty Papers

The intrinsic apoptosis pathway occurs through the release of mitochondrial cytochrome c to the cytosol, where it promotes activation of the caspase family of proteases. The observation that tRNA binds to cytochrome c revealed a previously unexpected mode of apoptotic regulation. However, the molecular characteristics of this interaction, and its impact on each interaction partner, are not well understood. Using a novel fluorescence assay, we show here that cytochrome c binds to tRNA with an affinity comparable with other tRNA-protein binding interactions and with a molecular ratio of ∼3:1. Cytochrome c recognizes the tertiary structural features of tRNA, particularly in …

Role Of Microrna-21 In Atherogenesis., Rihab Hamed-Berair

Electronic Theses and Dissertations

MicroRNA-21 (miR-21) is an evolutionarily conserved microRNA, abundant in most cardiovascular tissues. It has been implicated in the pathogenesis of several cardiovascular diseases including restenosis, myocardial infarction, and heart failure. However, little is known about the contribution of miR-21 in atherosclerosis. My data show that expression of miR-21 is increased by >1.5-fold in murine atherosclerotic lesions and by 1.5-2.0-fold in the macrophages of Western diet (WD)-fed LDLR-KO mice (for 12-20 weeks). In vitro, LDL, oxidized LDL, acetylated LDL and LPS induced miR-21 by 2-4-fold and down-regulated its target protein, PDCD4, in bone marrow-derived macrophages. Basally, macrophages isolated from miR-21-KO …

Investigation Of Novel Functions For Dna Damage Response And Repair Proteins In Escherichia Coli And Humans, Benjamin A. Hilton

Electronic Theses and Dissertations

Endogenous and exogenous agents that can damage DNA are a constant threat to genome stability in all living cells. In response, cells have evolved an array of mechanisms to repair DNA damage or to eliminate the cells damaged beyond repair. One of these mechanisms is nucleotide excision repair (NER) which is the major repair pathway responsible for removing a wide variety of bulky DNA lesions. Deficiency, or mutation, in one or several of the NER repair proteins is responsible for many diseases, including cancer. Prokaryotic NER involves only three proteins to recognize and incise a damaged site, while eukaryotic NER …

Deciphering The Role Of Glycine134 In The Human Acidic Growth Factor-1’S Binding To Heparin, Adam W. Burroughs

Chemistry & Biochemistry Undergraduate Honors Theses

Human acidic fibroblast growth factor 1 (FGF-1) is a potent modulator of cell survival and exhibits a universal role in various physiological processes. Though potent, FGF-1 unbound to heparin is known to show a poor thermal stability and a relatively short in vivo half-life. Much is known about the structure and relation of FGF-1 with heparin yet there is still unknown information regarding the exact role of heparin in stabilizing FGF-1. Thus, the aim of this study is to mutate glycine at position 134 to glutamic acid in wild type FGF1. G134 is located in the heparin binding pocket, thus …

Interaction Between Two E3 Ligases, Nedd8ylated Cullin And Hhari, Kheewoong Baek

Theses and Dissertations (ETD)

RBR (RING1-in between RING-RING2) is a special type of E3 ubiquitin ligase containing three zinc-binding RING (Really Interesting New Gene) domains, while adopting mechanisms of HECT (Homologous to E6-AP Carboxyl Terminus) for substrate ubiquitination. Most well known RBRs include Parkin and HOIP, which are associated with Parkinson’s disease and innate immune deficiency. However, it is not well known how the RBR proteins gain activity, as they are known to be autoinhibited. Here I show that a specific F430A, E431A, E503A triple mutation of RBR protein HHARI (Human homologue of Ariadne) and its interaction with NEDD8ylated cullin RING ligase can both …

Pten Signaling In Regulatory T Cells And Inflammatory Disease, Sharad Krishna Shrestha

Theses and Dissertations (ETD)

Regulatory T (Treg) cells suppress CD4+ T cell responses during homeostasis and inflammation to prevent autoimmunity and other immune disorders. Although the transcriptional and epigenetic programs impacting Treg cell function have been extensively studied, the signaling and metabolic pathways underlying Treg stability and function are not fully understood. In this study, we determined the role of the phosphatase PTEN in Treg cells. We found that specific depletion of PTEN in Treg cells results in excessive TH1 and T follicular helper cells (TFH) responses, associated with elevated germinal center (GC) B cells and spontaneous development of autoimmune and lymphoproliferative disease in …

A Parp1-Erk2 Synergism Is Required For The Induction Of Ltp., L Visochek, G Grigoryan, A Kalal, H Milshtein-Parush, N Gazit, I Slutsky, A Yeheskel, A Shainberg, A Castiel, R Seger, Marie-France Langelier, F Dantzer, Pascal Jabbour Md, M Segal, M Cohen-Armon

Department of Biochemistry and Molecular Biology Faculty Papers

Unexpectedly, a post-translational modification of DNA-binding proteins, initiating the cell response to single-strand DNA damage, was also required for long-term memory acquisition in a variety of learning paradigms. Our findings disclose a molecular mechanism based on PARP1-Erk synergism, which may underlie this phenomenon. A stimulation induced PARP1 binding to phosphorylated Erk2 in the chromatin of cerebral neurons caused Erk-induced PARP1 activation, rendering transcription factors and promoters of immediate early genes (IEG) accessible to PARP1-bound phosphorylated Erk2. Thus, Erk-induced PARP1 activation mediated IEG expression implicated in long-term memory. PARP1 inhibition, silencing, or genetic deletion abrogated stimulation-induced Erk-recruitment to IEG promoters, gene …

Synthesis And Characterization Of Nanoparticle-Coupled Proteins In Human Serum Albumin, Kyle M. Mahoney

Honors College Theses

Recently, cancer has become an ever-growing issue and has led to many researchers attempt to unravel the mystery of the disease. This research has led to a promising field of treatment: nanotechnology-coupled pharmaceuticals. Nanoparticles act as a whole unit when in conjugation with other molecules and add to the carrier molecule, most often proteins, benefits the nanoparticles themselves possess. One such carrier protein that can be conjugated with nanoparticles is Human Serum Albumin (HSA). Albumin is of interest in cancer research for two reasons: it is native to the human vasculature so it does not elicit immunological reactions, and it …

Nrp2 Transcriptionally Regulates Its Downstream Effector Wdfy1., Samikshan Dutta, Sohini Roy, Navatha S. Polavaram, Gustavo B. Baretton, Michael H. Muders, Surinder K. Batra, K Datta

Journal Articles: Biochemistry & Molecular Biology

Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)-protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, …