Life Sciences Commons^™

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 …

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 …

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. …

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 …

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, …

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, …

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 …

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 …

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, …

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 …

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 …

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 …

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 …