Biochemistry, Biophysics, and Structural Biology Commons^™

Sequence Properties Of An Intramolecular Interaction That Inhibits P53 Dna Binding, Emily Gregory, Gary W. Daughdrill

Molecular Biosciences Faculty Publications

An intramolecular interaction between the p53 transactivation and DNA binding domains inhibits DNA binding. To study this autoinhibition, we used a fragment of p53, referred to as ND WT, containing the N-terminal transactivation domains (TAD1 and TAD2), a proline rich region (PRR), and the DNA binding domain (DBD). We mutated acidic, nonpolar, and aromatic amino acids in TAD2 to disrupt the interaction with DBD and measured the effects on DNA binding affinity at different ionic strengths using fluorescence anisotropy. We observed a large increase in DNA binding affinity for the mutants consistent with reduced autoinhibition. The ΔΔG between DBD and …

College Of Natural Sciences Newsletter, January 2022, College Of Natural Sciences

College of Natural Sciences Newsletters and Reports

Volume 3, Issue 1

Page 1 Dean's Message
Page 2 Awards & Recognition
Page 3 Outreach in Harrisburg, SD
Page 4 Geography Alumni Named Among 'Highly Cited Researchers', 53rd Annual Geography Convention
Page 5 Geography Convention Speakers, Brookings/SDSU Day
Page 6 Media Coverage of Natural Sciences
Page 7 Open PRAIRIE Data
Page 8 Fall 2021 Dean's List
Page 9 Fall 2021 Dean's List, cont.

The Effects Of Neuronal Growth Factors On Lps-Activated Schwann Cells, Caitlyn E. Henry, Peyton Kimmel, Angela Asirvatham Ph.D.

Student Research Poster Presentations 2022

Schwann cells (SCs) are the principal support cells of neurons in the peripheral nervous system, that both myelinate axons for the rapid conduction of electrical impulses as well as assist in axonal repair during nerve injury. During nerve injury, SCs secrete tumor necrosis factor alpha (TNF-α)^1,5,6 and other proinflammatory mediators^1,6, attracting macrophages to the site of injury to induce inflammation and clear myelin debris.^1,6 Once the debris is cleared, the neuron stimulates SC proliferation by secreting neuronal mitogens, such as heregulin^3,4, and an unknown factor that activates the cAMP pathway³, an important …

Simulation Of An Inflammatory Model Using Schwann Cells, Caitlyn Henry, Peyton Kimmel, Angela Asirvatham

Student Research Poster Presentations 2022

During peripheral nerve injury, the myelin surrounding the neuronal axons is damaged, initiating an inflammatory response to remove myelin debris. Once myelin debris is cleared, Schwann cells acquire a proliferating phenotype which allows them to grow and divide so that remyelination can occur. The neuron stimulates Schwann cell division by secreting growth factors, like heregulin, and an unknown growth factor that activates the cAMP pathway. Although the role of cAMP in axonal regeneration is well-known, not much has been explored about its function in Schwann cells during nerve injury and inflammation. To simulate an inflammatory environment, the S16 Schwann cell …

Exploring The Roles Of Stress, Codon Usage, And Rna Modifications In Myotonic Dystrophy Type 1, Afrooz Golestanian

Legacy Theses & Dissertations (2009 - 2024)

Myotonic dystrophy (DM), the most common form of muscular dystrophy, is a neuromuscular disease caused by microsatellite repeat expansions. It can represent a multi-systemic autosomal dominant disease with DM1 and DM2 subtypes. A cytosine-thymine-guanine (CTG) triplet repeat in the 3’ untranslated region (3’UTR) of myotonic dystrophy protein kinase (DMPK) gene causes DM1 disease, which leads to the production of a longer, abnormal and toxic mRNA. The toxic DMPK mRNA sequester the splicing proteins such as Muscle blind-like (MBNL) and rbFOX which leads to gene expression alteration. Repeat associated non-AUG (RAN) translation also occurs in DM1. Mitochondrial dysregulation has also been …

Salivary Gland Stromal Heterogeneity And Epithelial Controls, Nicholas L. Moskwa

Legacy Theses & Dissertations (2009 - 2024)

Organogenesis is the process organs go through where cellular communications coordinate all a developing organ needs. What organs need are more cells, in the right place, doing the right job. In the salivary gland, we know that stromal cells are important for organogenesis and that they coordinate the epithelium’s form and functions. However, specific stromal contributions have focused on epithelial quantity and placement. There is less information about how the stroma directs the epithelium towards certain functions. Here we used organoids as a model for understanding what stromal signaling directs epithelial cell fate. We found that stromal cell state is …

A Study Of Cobalt (Iii) Oxide Nanoparticle Delivery Of Sirna Molecules Directed Against Signaling Intermediates Of The P2y2 Receptor, Rachel Blair Stroud

MSU Graduate Theses

G protein-coupled receptors are evolutionarily ubiquitous sensors of extracellular signals, propagating intracellular signal cascades through heterotrimeric G proteins. P2Y₂ receptors are GPCRs which are activated by extracellular nucleotides to mediate signaling cascades via Gαq coupling. Many GPCRs are subject to a common mechanism for signal termination involving phosphorylation of the C-terminal tail followed by β-arrestin binding and subsequent endocytic internalization of the complex. This effect has been described for the P2Y₂ R in the 1321N1 astrocytoma cell line, and UTP-induced activation and desensitization profiles have been previously defined. There is need to develop molecular vehicles for safe and …

Characterizing The Relationship Of Lgl1 And Akt In Migration Of Murine Neural Stem And Progenitor Cells, Natalie Pedicino

Cal Poly Humboldt theses and projects

Asymmetric cell division and migration are critical for neural stem cell differentiation and brain development. When these processes are dysregulated in neural progenitor cells (NPCs), developmental defects and diseases like glioma can result. Lgl1 is a tumor suppressor gene that was first characterized in Drosophila neuroblasts (Strand et al., 1994). It is best known for its regulation of asymmetric cell division through its association with the Par complex. The PI3K/AKT signaling cascade is involved in cellular migration and is also regulated by Par signaling. Unpublished data from the Sprowles laboratory suggests a potential role of Lgl1 in migration and other …

Review Of The Effects Of Asphalt Fume Emission (Vocs And Pahs) In Vitro, In Vivo And Human Studies, Omran Taqi, Nastassja Lewinski, Elham Fini, Eran Rozewski, Judith Klein-Seetharaman

Undergraduate Research Posters

Review of the effects of Asphalt fume emission (VOCs and PAHs) in vitro, in vivo and human studies

Omran Taqi, Nastassja Lewinski¹

1) Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA

Background

Asphalt is abundantly available around human operations including road paving and roofing sites. However, their emissions and fumes (specifically volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs)) have been found to have adverse effects on health. Asphalt fumes are a class 2A carcinogen and exposure can increase the risk of lung cancer, asthma, headache, fatigue, and other cardiovascular diseases.

Methods

We used …

Further Investigation Of The Initiating Mechanism Of The Type I Collagen Glomerulopathy, Matthew James Freese

MSU Graduate Theses

The progressive accumulation of collagen and other extracellular matrix proteins in the renal mesangium results in fibrosis, glomerulosclerosis, and eventual renal failure. Mice deficient in integrating α2(I) collagen into the type I collagen structure, termed Col1a2-deficient mice, model kidney fibrosis through the condition Type I Collagen Glomerulopathy, because homotrimeric type I collagen accumulates extracellularly in the mesangium of renal glomeruli. Accumulation of homotrimeric type I collagen compresses blood vessels in glomeruli, which reduces filtration, increases pressure, and results in fibrosis. Picrosirius red (PSR) staining was used on Col1a2 deficient and wildtype mice to evaluate collagen deposition. Histological evaluation and …

Genetic Analysis Of Adhesion Protein Elmo3 In Arabidopsis Thaliana, Garrison Asper

Honors Projects

The Extracellular Matrix (ECM) between plant cells is vital for structure, development, and intercellular adhesion. A pectin rich layer in between cells, the middle lamella, is largely responsible for regulating the adhesive properties of adjacent plant cells. Homogalacturonan (HG) pectin, the most common, is synthesized in the Golgi and secreted into the ECM where it undergoes calcium crosslinking, increasing its adhesive properties. Mutations in proteins essential for HG synthesis can reveal a severe adhesion defective phenotype, where the hypocotyls of dark grown Arabidopsis exhibit cell sloughing, curling, and general disorganization. A family of five ELMO proteins are suspected to act …

An Investigation Into The Mechanism Of Proteasome Dysfunction In Neurodegenerative Disease And The Biological Impact Of Proteasome Hyperactivation In C. Elegans, Raymond T. Anderson

Graduate Theses, Dissertations, and Problem Reports

Aging is an inevitable process that occurs as humans grow older. It is characterized by the chronological accumulation of cellular damage over time leading to functional decline as an organism grows older. Several processes are thought to contribute to the aging phenomenon, but one of the most prolific of these is the disruption of protein homeostasis (proteostasis). The collapse of proteostasis can lead to accelerated aging and the development of age-related diseases including devastating neurodegenerative diseases (NDs) like Alzheimer and Parkinson disease. Virtually all NDs are characterized by the buildup of proteins in and around neurons resulting in neuronal death …

Ero1Α Promotes Tumorigenesis In Egfr Driven Nsclc, Brennan D. Johnson

Graduate Theses, Dissertations, and Problem Reports

Non-Small Cell Lung Cancer (NSCLC) is a pulmonary malignancy most commonly associated with smoking, or exposure to asbestos or Radon. Approximately, 1.6 Million deaths occur each year due to lung cancer. Lung Cancer is categorized by two main types, Small Cell Lung Cancer (SCLC) and NSCLC. NSCLC accounts for approximately 85% of all lung cancer cases and is subdivided into three sub-categories: Adenocarcinoma, the most common and leading cause of death in the United States; Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma. Though NSCLC treatment regimens have shown increasing clinical benefit over the last two decades with targeted therapies. …

Phip Variants Associated With Chung–Jansen Syndrome Disrupt Replication Fork Stability And Genome Integrity, Neysha Tirado-Class, Caitlin Hathaway, Wendy K. Chung, Huzefa Dungrawala

Molecular Biosciences Faculty Publications

Chung–Jansen syndrome (CJS) is a rare, autosomal dominant disorder characterized by developmental delay, intellectual disability/cognitive impairment, behavioral challenges, obesity, and dysmorphic features. CJS is associated with heterozygous variants in PHIP (Pleckstrin-Homology Interacting Protein), a gene that encodes one of several substrate receptors for Cullin4-RING (CRL4) E3 ubiquitin ligase complex. Full-length PHIP, also called DCAF14, was recently identified to function as a replication stress response protein. Herein, we report the identification of two PHIP missense variants identified by exome sequencing in unrelated individuals with CJS. The variants p.D488V and p.E963G occur in different functional elements of DCAF14-WD40 repeat domain and pleckstrin …

Functionalization Of Chitosan Based Microparticles For In Vitro 3d Culture Of Human Liver Cells, William Imes

Williams Honors College, Honors Research Projects

Previous work involving 3D culture of human liver cells with fluorinated chitosan based microparticles has shown that their incorporation provides needed structural cues that the culture of cells alone does not provide, such as increased gas transport. However, using bare microparticles to grow large 3D cellular structures is not practical as they tend to collapse before any meaningful research can be done on them. It is proposed that this is because of the lack of extracellular matrix (ECM)components within pure cell culture in vitro, which in their absence cannot adequately facilitate biochemical communication and adhesion between cells. It is …

Sources And Therapeutic Strategies Of Mesenchymal Stem Cells In Regenerative Medicine, Mohamed M. Kamal, Dina H. Kassem

Pharmacy

During the past decade, mesenchymal stem cells (MSCs) have made their mark as a potential weapon in regenerative medicine. Since their first isolation by Friedenstein in the late 1970s of the last century, MSCs have opened new avenues in the field of regenerative medicine. The main fascination about MSCs lies in their ease of isolation and large ex vivo expansion capacity, as well as demonstrated multipotency and immunomodulatory activities. Basically, several reports have proved that MSCs isolated from different sources possess different characteristics and potentials. In addition, the mechanisms by which these cells can help regenerate tissues and treat several …

Alternative Splicing Regulates The Innate Immune Response To Viral Infection, Luke A. White

Graduate Student Theses, Dissertations, & Professional Papers

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus that infects humans and livestock in sub-Saharan Africa and the Arabian peninsula, causing disease ranging from a mild flu-like illness to liver damage, blindness, hemorrhagic fever, death, and, especially in livestock animals, high rates of abortive pregnancies. There is no approved vaccine for RVFV, and as a disease with a high rate of spread that causes severe illness, it is listed as a Category A pathogen by the USA CDC. A better understanding of RVFV’s molecular virology will be instrumental to combating RVFV as climate change causes its mosquito host …

The Role Of Irf-1 In Spontaneous Mouse Glioma, Aakash B. Vaidya

Theses and Dissertations

Glioblastoma Multiforme has been shown to be one of the deadliest primary brain cancers. One of the reasons why GBM is so deadly, is a unique immunosuppressive tumor microenvironment that promotes GBM growth and progression. Both astrocyte and microglia have been implicated in immunosuppression. In this study, we explored the role of Interferon Regulatory Factor 1 (IRF-1) in astrocytes and glioma cells on the growth of spontaneous glioma tumors. IRF-1 is regulated by the JAK/STAT pathway and induces expression of Programmed death ligand 1 (PD-L1). PD-L1 downregulates immune responses to glioma. We found that IRF-1 had no effect on spontaneous …

Development Of Novel Pyridazine Derivatives And Drug Delivery Systems Against Dengue, Janae A. Culmer

Electronic Theses and Dissertations

The lack of approved vaccines, medications and treatment regimens has significantly contributed to the rapid spread of mosquito-borne viruses such as Dengue and Zika virus. The complex immunopathology of these viruses presents limitations for the development and implementation of a definitive, safe and effective approach to combat infections.Previous research has demonstrated that vector control strategies such as the elimination of larval habitats, larviciding with insecticides, the use of biological agents and the application of adulticides have been unsuccessful in the reduction of viral transmission leading to the need for the continued development of antivirals. This research proposes an approach for …

Characterization Of Cofilin And Its Potential Role In The Epha4 Pathway, Brian Donald Condron

Master's Theses and Doctoral Dissertations

EphA4 is a receptor tyrosine kinase that is responsible for cellular adhesion and locomotion using repulsion signaling in early development of Xenopus laevis. EphA4 regulates cellular locomotion by controlling proteins within its signal transduction pathway, which may include the protein cofilin. Cofilin actively severs and removes actin monomers, thus altering the actin cytoskeleton, leading to the cessation of cellular crawl. During the gastrulation phase of embryonic development, individual cells are relocating to create the three primary germ layers of the organism. Failure of this process to occur results in attrition of the embryos, frequently by way of embryonic exogastrulation. …

Thyroid Hormone Receptor Beta Inhibits Pi3k Signaling And Glycogen Metabolism In Anaplastic Thyroid Cancer, Cole Davidson

Graduate College Dissertations and Theses

Thyroid cancer is the most common endocrine malignancy, and the global incidence has increased rapidly over the past few decades. While differentiated thyroid cancers often respond to standard therapies, there are no durable long-term treatment options for anaplastic thyroid cancer (ATC). The limited treatment options highlight a need for a deeper understanding of the molecular signaling in these aggressive tumors for development of more effective therapies.Non-steroidal nuclear receptors, such as thyroid hormone receptors (TRs), are an emerging class of therapeutic targets and tumor suppressors in thyroid and other cancers.Loss of expression of the tumor suppressor thyroid hormone receptor beta (TRβ) …

Functional Characterization Of Cancer-Associated Dna Polymerase Ε Variants, Stephanie R. Barbari

Theses & Dissertations

Replicative DNA polymerases ε (Polε) and δ (Polδ) achieve high fidelity DNA synthesis through a precise balance of polymerization and exonucleolytic proofreading. Errors that escape proofreading are corrected by DNA mismatch repair (MMR). Ultramutated human cancers with proficient MMR carry alterations in the exonuclease domain of Polε, which were initially predicted to abolish proofreading. However, functional studies in yeast of the most recurrent Polε-P286R variant suggested defects beyond a loss of exonuclease activity. Indeed, biochemical analysis of the yeast Polε-P286R analog revealed increased polymerization capacity in addition to decreased proofreading, which enables efficient mismatch extension and bypass of replication-blocking non-B …

Nuclear Receptor Coactivator 3 In Endoplasmic Reticulum Stress And Stress Granule Dynamics In Pancreatic Cancer, Andrew Kisling

Theses & Dissertations

Pancreatic cancer is predicted to be the second-leading cause of cancer-related deaths within the next decade. Nuclear receptor coactivator 3 (NCOA3/SRC3/AIB1) regulates an array of metabolic and signaling pathways and has been established by our group and others as a critical regulator pancreatic cancer progression and metastasis. A recent study demonstrated NCOA3 regulation by the IRE1α-XBP1 axis of the unfolded protein response (UPR), suggesting a link between NCOA3 and cellular stress management. Furthermore, NCOA3 has been shown to directly bind to a scaffolding protein of stress granules (SGs). Since SG assembly is regulated by the UPR, we hypothesized that NCOA3 …

A Pkcα-Mediated Growth Suppressive Mek-Erk Signaling Axis In Intestinal Epithelial Cells, Navneet Kaur

Theses & Dissertations

Members of the protein kinase C (PKC) family of serine/threonine kinases are involved in regulation of fundamental cellular functions, including proliferation, differentiation, survival, migration, and transformation. Increasing evidence points to anti-proliferative and tumor suppressive role of PKCs. Our laboratory and others have reported that the classical PKC isozyme, PKCαnegatively regulates proliferation and tumorigenesis in the intestinal epithelium. Our laboratory has further determined that PKCα signaling induces a program of cell cycle withdrawal in intestinal epithelial cells that involves downregulation of the pro-proliferative proteins, cyclin D1 and Id1, and upregulation of the cyclin dependent kinase (CDK) inhibitor, p21^Cip1. Unexpectedly, …

Probing The Role Of Astrocytes In The Pathology Of Fragile X Syndrome With Human Stem Cells, Baiyan Ren

Theses & Dissertations

Fragile X syndrome (FXS) is an X-linked neurodevelopmental disorder related to intellectual disability and the most common monogenic cause of autism spectrum disorder. FXS is mainly caused by an expansion of CGG repeats in the 5’-untranslated region of fragile X mental retardation 1 (FMR1) gene, leading to the loss of expression of fragile X mental retardation protein (FMRP). Astrocytes are the most abundant glial cells in the central nervous system (CNS). Loss of FMRP in astrocytes has been found to contribute to structural and functional synaptic deficits in the Fmr1-KO mouse model. The contribution of human astrocytes, however, to the …

Usp11 And Usp7 Deubiquitinases Regulate Sprtn Auto-Proteolysis And Sprtn-Mediated Dna-Protein Crosslink Repair, Megan C. Perry

Theses & Dissertations

DNA repair pathways that recognize and remove damaged DNA are vital for maintenance of genomic stability and prevention of tumorigenesis. Conversely, these pathways may be robust in tumor cells, thus diminishing the anti-cancer potential of available therapies. DNA-protein crosslinks (DPCs) are particularly deleterious DNA adducts that occur when proteins become irreversibly covalently bound to the DNA. DPCs represent a diverse group of lesions, as any protein can be crosslinked to the DNA duplex by non-specific crosslinking agents like reactive aldehydes and radiation. Additionally, functional DNA-binding proteins such as topoisomerases may become permanently crosslinked to DNA ends by abortive enzymatic processes …

Molecular Mechanisms Of Aberrant Protein Glycosylation In Pancreatic Cancer Stemness And Metastasis, Frank Leon

Theses & Dissertations

A myriad of genetic and other abnormal changes underlies the aggressiveness and dissemination properties observed in pancreatic cancer (PC). Aberrant protein glycosylation is a commonly observed feature in PC. The modification of protein O-glycosylation is mediated by glycosyltransferases, which attach and sequentially elongate monosaccharides on Serine/Threonine (Ser/Thr) motifs. Aberrant glycosylation is recognized as an emerging hallmark of cancer where a disruption in normal glycosylation results in irregular O-glycans.

This dissertation research has investigated the consequences of aberrant protein glycosylation on stemness and enhancement of metastatic properties in pancreatic ductal adenocarcinoma (PDAC). Several publications have reported aberrant O-glycosylation increases in oncogenic …

Dicer Represses Antiviral Innate Immunity Pathways In Mouse Embryonic Stem Cells, Chandan Gurung

Dissertations

Recent studies have demonstrated that embryonic stem cells (ESCs) are deficient in expressing type I interferons (IFN), the cytokines that play key roles in antiviral responses. However, the underlying molecular mechanisms and biological implications of this finding are poorly understood. In this study, I used a synthetic RNA-based assay that can simultaneously assess multiple forms of antiviral responses in ESCs. Dicer is an enzyme essential for RNA interference (RNAi), which is used as a major antiviral mechanism in invertebrates but not clear in vertebrates. RNAi activity is detected in wild-type ESCs but is abolished in Dicer knockout ESCs (D−/−ESCs) as …

Calmodulin Like 38 Is Required For Autophagy Of Hypoxia-Induced Cytoplasmic Rna Granules In Arabidopsis Thaliana, Sterling Field

Doctoral Dissertations

In response to the energy crisis resulting from submergence stress and hypoxia, the model plant Arabidopsis thaliana limits non-essential mRNA translation, and accumulates cytosolic stress granules. Stress granules are phase-separated mRNA-protein particles that partition transcripts for various fates: storage, degradation, or return to translation after stress alleviation. Another response by the plant cell to low oxygen stress is the induction of the turnover pathway autophagy. Stress granule regulation by autophagy occurs by a ‘granulophagy’ pathway in yeast and mammalian systems through which parts or whole stress granules are degraded. Whether this occurs in plants has not been investigated.

A connection …

Erecta Family Genes Regulate The Shoot Apical Meristem And Organ Formation, Daniel A. Degennaro

Doctoral Dissertations

Plants are sessile and must adjust their organ growth to their environments. A reservoir of stem cells in the shoot apical meristem (SAM) supplies cells for differentiation into organs. The SAM must balance organ production with stem cell maintenance. The ERECTA family (ERfs) encodes the leucine-rich repeat receptor-like kinases ERECTA (ER), ERECTA-LIKE 1 (ERL1), and ERL2. ERf signaling regulates organ initiation and stem cell maintenance. Results presented in this work include the following:

1) WUSCHEL (WUS) and CLAVATA3 (CLV3) make up a negative feedback loop to maintain SAM size. WUS and CLV3 expression localization is critical for …