Cell and Developmental Biology Commons^™

Targeting Oncogenic Protein Sythesis In Myc-Driven B Cell Lymphoma, Xuan Zhang

Theses & Dissertations

Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive tumors of mature B cells that can be distinguished based on histomorphological, phenotypic, and genetic features. B-cell lymphoma unclassifiable, with features intermediate between BL and DLBCL (BCL-U) is a subset of mature B cell lymphoma contains one or more features that overlap BL and DLBCL. Previous molecular analyses prove there is a biological continuum between BL and DLBCL based on the activity of MYC. Herein, in order to resolve the molecular heterogeneity of BCL-U, we tested whether a targeted expression profiling panel could categorize tumors as BL and DLBCL. …

Human Leukocyte Antigen (Hla) Class I Molecule Components And Amyloid Precursor-Like Protein 2 (Aplp2): Roles In Pancreatic Cancer Cell Migration, Bailee Sliker

Theses & Dissertations

Human leukocyte antigen (HLA) class I molecules are composed of a light chain (beta 2-microglobulin (β₂m)) and HLA heavy chain. The heavy chains of these molecules have three different isotypes (–A, -B, and –C) and are highly polymorphic with thousands of sequence variations termed allotypes. The best-known role for these molecules is within the immune system, however, recent research implicates components of this molecule can function outside of this known immune role by contributing to cell migration. However, no studies have been published thus far investigating this non-immune function in pancreatic cancer. Therefore, I examined the role of …

Identification Of Pathways Required For The Survival Of Inversion(16) Acute Myeloid Leukemia, Yiqian Wang

Theses & Dissertations

Inversion of chromosome 16 [inv(16)] acute myeloid leukemia (AML) generates a fusion gene CBFB-MYH11. Approximately half of inv(16) AML patients eventually relapse mainly due to the existence of leukemia stem cells (LSCs). Previous work using a Cbfb-MYH11 knockin mouse model showed that the LSCs are enriched within CSF2RB^- population. Another gene upregulated by Cbfb-MYH11 encodes the cytokine receptor IL1RL1. Using Cbfb-MYH11 knockin mice, we showed that LSCs exist in multiple sub-populations defined by their immunophenotype, and IL1RL1 is expressed by cell populations with high LSC activity. We also found that treatment of IL-33, the ligand for IL1RL1, promoted …

The Role Of Ros In The Progression And Treatment Of Castration-Resistant Prostate Cancer, Dannah R. Miller

Theses & Dissertations

Prostate cancer is the second leading cause of cancer-related deaths in U.S. men, primarily due to the development of castration-resistant (CR) prostate cancer (PCa), of which there are no effective treatment options. Reactive oxygen species (ROS) plays a critical role in prostate carcinogenesis, including the progression of the CR PCa phenotype. ROS regulates both cell proliferation and apoptosis; a moderate increase in ROS can promote proliferation; however, a substantial rise in ROS levels will result in apoptosis. Oxidase p66Shc is elevated in clinical PCa cells and has been associated with a metastatic phenotype of CR PCa cells, promoting PCa cell …

Developing Targeted Therapy Against Pancreatic Cancer, Garima Kaushik

Theses & Dissertations

Not available.

Med12 Mutations Promote Castration-Resistant Prostate Cancer Through Hyperactivated Gli3/Shh Signalling, Soundharrya Muthukumar

Theses & Dissertations

When cells of the prostate gland start growing uncontrollably, it results in cancer due to genetic aberrations. The development and progression of prostate cancer depend on androgenic stimulation. Although prostate cancer is temporarily treated by depriving a tumor of androgen, the patient relapses getting a castration-resistant form of the disease called castration-resistant prostate cancer (CRPC). CRPC can specifically develop through crosstalk of androgen receptor signalling pathways. One such pathway that is of specific interest in this paper is the MED12 regulated SHH signalling pathway. The mediator is a signal processor that helps in the transduction of gene-specific transcription factors to …

Delineation Of New Mechanisms Of Dna Double Strand Break Repair, Songli Zhu

Theses & Dissertations

DNA damage is frequently induced in cells by both endogenous and exogenous agents. DNA damage, particular double strand breaks (DSBs) may lead to genomic instability, and the progression of cancer, aging, neurodegeneration, and other human diseases. The cell employs two major DSB repair pathways, including homologous recombination (HR) and Non-homologous end joining (NHEJ), but the detailed mechanisms of DSB repair remain to be further revealed.

In the first part of this study, we characterized a plasmid-based assay to investigate NHEJ repair in Xenopus egg extracts. Our data argued for a preference for the precise repair by the NHEJ machinery and …

Towards An In Vitro Model Of Testing Osteoblast Cellular Function In Contact With Various Surfaces, Raheleh Miralami

Theses & Dissertations

Past studies have shown that the success of total joint replacements depends on the biocompatibility of orthopaedic materials, which can be improved by modifying the implant surface. However, the exact roles of these modifications and their effective mechanisms are poorly understood. The objective of this study was to develop and evaluate a model system to investigate the impact of nano-structured surfaces, produced by the ion beam-assisted deposition (IBAD) technique, on biomarkers of osteointegration using an in vitro model. The IBAD technique was employed to deposit zirconium oxide (ZrO₂), Titanium oxide (TiO₂), and Titanium (Ti) nano-films on …

Regulation Of Canonical And Non-Canonical Hippo Pathway Components In Mitosis And Cancer, Seth Stauffer

Theses & Dissertations

The Hippo pathway is conserved regulator of organ size through control of proliferation, apoptosis, and stem-cell self-renewal. In addition to this important function, many of the canonical signaling members have also been shown to be regulated during mitosis. Importantly, Hippo pathway components are frequently dysregulated in cancers and have attracted attention as possible targets for improved cancer therapeutics. Further exploration of Hippo-YAP (yes-associated protein) signaling has revealed new regulators and effectors outside the canonical signaling network and has revealed a larger non-canonical network of signaling proteins in which canonical Hippo pathway components crosstalk with important cellular homeostasis and apoptosis signaling …

Intra- And Inter-Molecular Signaling In A Cardiac Connexin: Role Of Cytoplasmic Domain Dimerization And Phosphorylation, Andrew J. Trease

Theses & Dissertations

As critical mediators of cell-to-cell communication, gap junctions (GJs) are comprised of membrane channels that directly link the cytoplasm of adjacent coupled cells thereby allowing for the passage of ions, small metabolites, and secondary messengers. Each channel is formed by the apposition of two connexons from adjacent cells, each composed of six connexin (Cx) proteins. Each GJ channel functions to promote signal propagation and synchronization of cells and tissues in organs. Furthermore, GJs are essential for proper propagation of cardiac action potentials from one cell to the next, leading to the coordinated contraction and relaxation of heart muscle powering circulation. …

Foxm1 Expression And Contribution To Genomic Instability And Chemoresistance In High-Grade Serous Ovarian Cancer, Carter J. Barger

Theses & Dissertations

High-grade serous ovarian cancer (HGSC) is the most common and deadly subtype of epithelial ovarian cancer. Understanding the molecular basis of HGSC will improve diagnosis and treatment approaches. The Cancer Genome Atlas (TCGA) discovered that Forkhead Box M1 (FOXM1) transcription factor activation is the second most frequent molecular alteration in HGSC (84% of cases), second only to mutations of TP53 (100%). We subsequently defined several genetic mechanisms that underlie increased FOXM1 expression in HGSC, including genomic amplifications and RB-E2F deregulation, and showed that FOXM1 promotes cell cycle progression in cell models relevant to HGSC.

TCGA analyses revealed that genomic instability, …

Determinants Of Multi-Scale Patterning In Growth Plate Cartilage, Alek Erickson

Theses & Dissertations

ABSTRACT

Functional architectures of complex adaptive systems emerge by dynamic control over properties of individual components. During skeletal development, growth plate cartilage matches bone geometries to body plan requisites by spatiotemporally regulating chondrocyte actions. Bone growth potential is managed by the proximodistal patterning of chondrocyte populations into differentiation zones, while growth vectors are specified by the unique columnar arrangement of clonal groups. Chondrocyte organization at both tissue and cell levels is influenced by a cartilage-wide communication network that relies on zone-specific release and interpretation of paracrine signals. Despite genetic characterization of signaling interactions necessary for cartilage maturation, the regulatory mechanisms …

The Role Of Hippo Pathway In Mitosis And Cancer, Xingcheng Chen

Theses & Dissertations

The Hippo signaling pathway has been recently elucidated as a tumor suppressor pathway controlling cell proliferation and apoptosis. The core of this pathway is a kinase cascade which contains MST1/2 (Mammalian sterile 20-like kinase 1/2), LATS1/2 (large tumor suppressor 1/2) and downstream effector named Yes-associated protein (YAP). MST1/2 transduce their kinase activity mainly through directly phosphorylating LATS1/2. Once phosphorylated and activated, LATS1/2 subsequently phosphorylate and inhibit YAP from translocating to nucleus. Current studies involving the Hippo pathway focus on determining its oncogenic role in various organs/tissues. While those studies provide important insight into the tumor suppressor properties of this pathway, …

Functional Signature Ontology-Based Identification And Validation Of Novel Therapeutic Targets And Natural Products For The Treatment Of Cancer, Beth Neilsen

Theses & Dissertations

Multiple studies have revealed that Ras-driven tumors acquire vulnerabilities by adapting cellular mechanisms that promote uncontrolled proliferation and suppress apoptosis. Kinase Suppressor of Ras 1 (KSR1) modulates ERK activation downstream of oncogenic Ras, and knockdown of KSR1 selectively kills malignant, Ras-driven cancer cells, but does not kill immortalized, non-transformed human colon epithelial cells (HCECs). KSR1^-/- mice are fertile and phenotypically normal, but resistant to Ras-driven tumor formation suggesting KSR1 represents a vulnerability in cancer cells.

To identify additional vulnerabilities in cancer, a screening approach termed Functional Signature Ontology (FUSION) was used to screen 14,355 genes and 1,200 natural product …

The Beta-Catenin/Muc1.Ct Interaction In Pancreatic Cancer, Edwin Wiest

Theses & Dissertations

MUC1 is overexpressed in over 90% of pancreatic cancer cases, and its interaction with beta-catenin promotes progression of the disease. Various in vitro and in vivo methods show that beta-catenin and MUC1 interact by way of the cytoplasmic tail of MUC1 (MUC1.CT). This interaction occurs in the membrane of pancreatic cancer cells but is found to a smaller extent in the nucleus as well. Biophysical methods suggest that MUC1 interacts with beta-catenin through a sequence of amino acids in the tail of MUC1 that sit very near the transmembrane domain of MUC1. In pancreatic ductal adenocarcinoma cells, it appears that …

Connexin32: Sorting, Endocytosis And Assembly, Anuttoma Ray

Theses & Dissertations

Gap junctions (GJ)s are conglomeration of several cell-cell channels at cell-to-cell contact sites involved in the direct intercellular exchange of small growth regulatory molecules. Defects in assembly of GJ-forming proteins, called connexins (Cxs), are observed in many cancers, yet the molecular basis of this defect remains unknown. Connexin32 (Cx32) is expressed by the polarized cells in epithelia. The carboxyl-terminal tail (CT) of Cx32, although not required to initiate GJ formation, orchestrates several aspects of GJ dynamics, function and growth. Our studies have discovered that the CT of Cx32 harbors a tyrosine-based [YXXØ]-type and two dileucine-based [DE]XXXL[LI]-type motifs, which govern the …

Overcoming Tcf4-Driven Bcr Signaling In Diffuse Large B-Cell Lymphoma, Keenan Hartert

Theses & Dissertations

Diffuse Large B-cell Lymphoma (DLBCL) is the most common subtype of lymphoma. Despite a cure rate of 40% with standard R-CHOP therapy, patients that refract or relapse are subject to a dismal prognosis. Cases of DLBCL can be classified by their molecular expression phenotype, with the GCB-like subtype aligning with the profile of a germinal center B-cell and the ABC-like subtype aligning to that of an activated B-cell. Aggressive disease is often characterized by high levels of B-cell Receptor (BCR) signaling. This pathway engages downstream kinases responsible for stimulating proliferation and survival that play a key role under the normal …

Elucidating The Roles Of Lunatic Fringe In Pancreatic Ductal Adenocarcinoma, Prathamesh Patil

Theses & Dissertations

Pancreatic cancer is an aggressive form of cancer that is very difficult to detect, treat resulting in a high rate of mortality. Understanding the molecular basis of pancreatic cancer and identifying new molecular targets for designing therapeutic interventions is paramount for improving outcomes in this disease. Notch signaling is a vital developmental signaling pathway that has been implicated to play both oncogenic and tumor suppressive roles in pancreatic cancer. Previous studies from other groups have shown that O-linked glycosylation of Notch signaling plays a key role in the regulation of Notch signaling. Lunatic fringe (Lfng) is one of the glycosyltransferases …

Functional Role Of Protein Kinase C Alpha In Endometrial Carcinogenesis, Alice Hsu

Theses & Dissertations

Protein kinase Cα (PKCα) is a member of the PKC family of serine/threonine kinases that regulate many fundamental cellular processes, including cell proliferation, differentiation, survival and transformation. The impact of PKCα on tumorigenesis, and whether it acts as an oncogene or tumor suppressor, has been debated over the years. The overall goal of this study was to establish the functional role of PKCα in endometrial carcinogenesis. Results from this study broaden our knowledge of PKCα signaling and add to our understanding of its role in tumor development.

As understanding of the role of PKCα signaling in the uterus is limited, …

Investigation Of P-Glycoprotein (Pgp) Induction By Pgp Substrates To Induce Paclitaxel Resistance In Ovarian Cancer Cells, Ryker Penn

Theses & Dissertations

The purpose of this study was to investigate the development of chemotherapeutic resistance to paclitaxel in ovarian cancer cells after treatment with drugs that are substrates for P-glycoprotein (PGP). A core concept of this experiment was to identify if PGP substrate drugs could also act as PGP inducers after prolonged treatment in SKOV-3 ovarian cancer cells. In order to test this, SKOV-3 cells were exposed to either fexofenadine, a PGP substrate used as an antihistamine, or the chemotherapeutic drug vinblastine. After 42 days of drug treatment, ABCB1 gene expression was measured by qRT-PCR. Analysis of ABCB1 expression in treated cells …

The Role Of Yes-Associated Protein 1 In Ovarian Physiology And Pathology, Xiangmin Lv

Theses & Dissertations

Ovarian granulosa cells are the major somatic components of the ovarian follicle. Proper proliferation and differentiation of ovarian granulosa cells are essential for successful follicle development. Accumulating evidence indicates that the Hippo-YAP signaling pathway plays critical roles in both development and tumorigenesis of several organs. The present study aims to investigate the role of Yes-associated protein 1 (YAP) in ovarian granulosa cell proliferation, differentiation, and malignant transformation. At first, we found that nuclear YAP (active) was highly expressed in proliferative granulosa cells, whereas cytoplasmic YAP (inactive) was detected mainly in terminally-differentiated luteal cells. Further studies suggested that endogenous YAP activity …

Transcriptome Profiling Of Cleft Palate Intgf-Beta3 Knockout Mice Alleles: Rna-Seq Analysis Of Tgf-Beta3 Mice, Kelsey White

Theses & Dissertations

Background: Orofacial clefts are the most common craniofacial birth defect with a complex, combinatorial etiology. Tgf-b3 regulates palatal fusion in mice; Tgf-b3 knockout mice have cleft palate (CP) lacking other major deformities. The genes downstream of Tgf-b3 during palatogenesis remain largely unexplored. Our objective was to analyze the global transcriptome changes and their contribution to CP and identify novel Tgf-b3 associated genes involved in formation of CP. We used RNA-sequencing to analyze and compare the whole transcriptome of Tgf-b3 alleles during palatal growth and fusion in mice.

Results: …

Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam

Theses & Dissertations

Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States, mainly due to metastasis to the distant organ sites. However, the molecular basis of CRC metastasis is poorly understood. Therefore, identification and characterization of novel potential anti-cancer therapeutic targets CRC is of urgent need. Utilizing a 2D-DIGE proteomics approach ezrin was identified as a protein that is differentially expressed between primary colon tumors xenografts, orthotopically implanted in athymic nude mice, and corresponding and liver metastatic deposits. Ezrin, a cytoskeletal protein belonging to the ezrin–radixin–moesin (ERM) family plays important roles in cell motility, invasion …

Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancers with a 5-year survival rate of only 8.2%. This is because PDAC is diagnosed in its advanced stages and is characterized by radio and chemotherapy resistance. Aggressiveness of PDAC tumors is attributed to its high metabolic phenotype, which is characterized by increased glycolysis rate and lactate secretion, while oxidative metabolism is reduced. These metabolic features are required to fulfill the biosynthetic demands of proliferating PDAC cells. However, this increase in metabolic activity results in acidification of the extracellular space because the dense fibrotic stroma of PDAC tumors limits …

Comparative Molecular Characterization Of Typical And Exceptional Responders In Glioblastoma, Kristin Wipfler

Theses & Dissertations

Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a small number of patients survive far beyond the median survival time. Investigation of these “exceptional responders” has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of copy number, methylation, gene expression, miRNA expression, and protein expression data sets from The Cancer …

Evaluation Of Aminopyrazole Analogs As Cyclin-Dependent Kinase Inhibitors For Colorectal Cancer Therapy, Caroline Robb

Theses & Dissertations

Colorectal cancer (CRC) remains one of the leading causes of cancer related deaths in the United States. Currently, there are limited therapeutic options for CRC patients, none of which focus on the cell signaling mechanisms controlled by members of the cyclin dependent kinase (CDK) family. CDK5 has been implicated in a variety of cancers, and most recently as a tumor promoter in CRC.

As such, we evaluated a compound developed by Pfizer, CP-668863 (a.k.a. 20-223), that inhibits CDK5 in neurodegenerative disorders. In our CRC xenograft model, 20-223 reduced tumor growth and tumor weight, indicating its value as a potential anti-CRC …

Identifying The Role Of Janus Kinase 1 In Mammary Gland Development And Breast Cancer, Barbara Swenson

Theses & Dissertations

The development of the postnatal mammary gland is tightly controlled by peptide hormones and cytokines. The signaling of these extracellular ligands through their corresponding receptors rely on Janus Kinases (JAKs) that activate downstream Signal Transducers and Activators of Transcription (STATs). The JAK/STAT signaling pathway is crucial for processes such as growth, proliferation, and cell survival of the epithelial tissue, but also for the breakdown and remodeling of the mammary gland via IL-6 class inflammatory cytokines (e.g. LIF and OSM). JAK1 and JAK2, which are expressed in the mammary gland, are thought to have redundant functions. However, our previous studies demonstrated …

Perturbing Anti-Apoptotic Proteins To Develop Novel Cancer Therapies, Jacob Contreras

Theses & Dissertations

The apoptotic pathway involves a tightly regulated network of proteins which respond to various stimuli. Previous studies have indicated Mcl-1 and Bcl-xL are intimately involved in determining cell fate, and if both are concurrently neutralized, it activates the apoptotic pathway. The inactivation of Bcl-xL and Mcl-1 as a mechanism to trigger the intrinsic apoptotic response can be used as a platform to develop therapeutic strategies to target cancer cells. The apoptotic pathway is largely dysregulated and often leads to therapy resistance in cancer cells. Although direct inhibitors of Bcl-xL have been developed and have advanced to clinical trials, development of …

Dopamine Levels In The Brain Of Rat Models Of Human Rheumatoid Arthritis, Amelia Stinson

Theses & Dissertations

Research Focus. Rheumatoid arthritis (RA) is a chronic, debilitating, autoimmune disease that causes the destruction of bone tissue and the articular structures of joints. At least 30% of RA patient populations have cognitive impairment. Acidic dopamine (DA) is the principal neuroimmunotransmitter that links the central nervous system and peripheral nervous system together. The aim of the present study was to determine the levels of DA and its two acidic metabolites: 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in arthritic induced rats, and whether their levels vary across four different parts of the brain: amygdala (AMG), front cerebral cortex (CX), hippocampus …

Molecular Mechanisms Of C-Terminal Eps15 Homology Domain Containing (Ehd) Protein Function, Kriti Bahl

Theses & Dissertations

Endocytic trafficking is not only an essential process for the maintenance of cellular homeostasis but also plays a vital role in regulating diverse cellular processes such as signaling, migration and cell division. The C-terminal Eps 15 Homology Domain proteins (EHD1-4) play pivotal roles in regulating distinct steps of endocytic trafficking. Among the EHDs, EHD2 is disparate both in terms of sequence homology (70%) and its subcellular localization at the caveolae. The crystal structure of EHD2 has been solved and it contains an unstructured loop consisting of two proline-phenylalanine (PF) motifs: KPFRKLNPF. However, the other paralogs EHD1, …