Digital Commons Network^™

Inhibition Of Lung Carcinogenesis By Polymethoxyflavones, Noppawat Charoensinphon

Open Access Dissertations

Lung cancer is the leading cause of cancer-related death worldwide. Exclusively found in citrus peels, the inhibitory effects of polymethoxyflavones (PMFs) on 3 human non-small cell lung cancer cells have been investigated. Results showed that monodemethylated PMFs at 5-position potently inhibited lung cancer cells than those of their permethoxylated counterparts. The inhibition of cancer cells caused by monodemethylated PMFs was associated with both extensive cell cycle arrest and apoptosis as a result of modulation of key oncogenic signaling proteins. Treatment with different bioactive compounds in combination may enhance inhibitory effects on lung cancer due to their synergistic interaction among these …

Med13p Prevents Stress-Independent Mitochondrial Hyperfragmentation And Aberrant Apoptosis Activation In Saccharomyces Cerevisiae By Controlling Cyclin C Nuclear Localization, Svetlana Khakhina

Graduate School of Biomedical Sciences Theses and Dissertations

During aging, and as a result of environmental changes, cells are exposed to elevated levels of reactive oxygen species (ROS). High ROS levels induce lipid oxidation, protein aggregation, mitochondrial hyperfragmentation, DNA damage and programmed cell death (PCD), also called apoptosis. PCD is a highly regulated process and its misregulation has been linked to neurodegenerative diseases and cancer development.

Our hypothesis is that cyclin C plays a role in the initiation of apoptosis. During normal conditions, cyclin C represses the transcription of stress response genes (SRG). In response to stress, cyclin C translocates to the cytoplasm where it facilitates mitochondrial hyperfragmentation …

Modulation Of Bax/Bak Dependent Apoptosis By Sirtuin 3 And Mitochondrial Permeability Transition By Sirtuin 4, Manish Verma

Graduate School of Biomedical Sciences Theses and Dissertations

Mitochondria are dynamic organelles that regulate a myriad of cellular functions, including energy production and metabolic regulation. Mitochondria are also a critical regulator of cell death signaling cascades modulating both apoptotic and necrotic cell death. However, what determines which cell death pathway is activated is still unclear. The mitochondrial/intrinsic pathway of apoptosis is dependent on the activation of pro-apoptotic proteins, Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). Once the integrity of outer mitochondrial membrane (OMM) is compromised, pro-apoptotic intermembrane space proteins like cytochrome c, Smac/Diablo, Omi/HtrA2 and AIF are released into the cytoplasm, which activates the post-mitochondrial …

A Novel Cardiac Function Of Sumo2/3 And Senp5 Dependent Pathway And Its Physiological Impact On Congestive Cardiomyopathy, Eun Young Kim

Dissertations & Theses (Open Access)

A Novel cardiac function of SUMO2/3 and SENP5 dependent pathway and its physiologic impact on congestive cardiomyopathy

Publication No.___________

Eun Young Kim, M.S.

Supervisory professor: Robert J. Schwartz, Ph.D.

SUMOylation regulates diverse cellular processes including transcription, cell cycle, protein stability, and apoptosis. Although SUMO1 has been extensively studied so far, relevance of SUMO2/3 is unclear, especially in heart. Here we show that failing heart induces SUMO2/3 conjugation. Increased SUMO2/3-dependent modification leads to congestive heart disease such as cardiac hypertrophy by promoting cardiac cell death. Calpain2 and Calpastatin as a novel SUMO2 targets have been known to be involved in mitochondrial-independent …

Novel Roles Of Replication Protein A Phosphorylation In Cellular Response To Dna Damage, Moises A. Serrano

Electronic Theses and Dissertations

Human replication protein A (RPA) is an eukaryotic single-stranded DNA binding protein directly involved in a variety of DNA metabolic pathways including replication, recombination, DNA damage checkpoints and signaling, as well as all DNA repair pathways. This project presents 2 novel roles of RPA in the cellular response to DNA damage. The first elucidates the regulation of RPA and p53 interaction by DNA-dependent protein kinase (DNA-PK), ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) in homologous recombination (HR). HR and nonhomologous end joining (NHEJ) are 2 distinct DNA double-stranded break (DSB) repair pathways. Here, we report that DNA-PK, the …

Susceptibility Of Apoptotic Cells To Hydrolysis By Spla2: Molecular Basis And Mechanisms Defined, Elizabeth Gibbons

Theses and Dissertations

Secretory phospholipase A2 hydrolyzes phospholipids at a lipid-water interface, resulting in pro-inflammatory products being released from cell membranes. Healthy cells are resistant to cleavage by this enzyme, but apoptotic cells become susceptible to its activity. Only bilayers with certain characteristics are able to be hydrolyzed. Most recently, studies in this lab have emphasized the idea that the biophysical state of the bilayer (in terms of lipid order, spacing, and fluidity) is relevant in determining the probability of one phospholipid escaping the membrane to be hydrolyzed. Prior to this study, it had been shown that apoptotic cells undergo biophysical alterations that …

Promoter Polymorphisms In Interferon Regulatory Factor 5, Daniel N. Clark

Theses and Dissertations

The promoter region of interferon regulatory factor 5 (IRF5) contains the rs2004640 T or G single nucleotide polymorphism (SNP) and a CGGGG indel. Both of these polymorphisms have been implicated as genetic risk factors for several autoimmune diseases, including systemic lupus erythematosus, whose pathology involves altered apoptosis and cytokine signaling. The polymorphisms' overall effect is to increase IRF5 levels. IRF5 is a transcription factor of several cytokines, including interferon, and is pro-apoptotic. Thus an alteration of cytokine levels and apoptosis signaling due to high IRF5 levels is the proposed source of autoimmune risk. Each of IRF5's four first exons (1A, …

Expression Of The Chemokine Receptor, Cxcr4, And Its Ligand, Sdf-1, Are Increased In Purkinje Cells Of The Multiple System Atrophy Cerebellum, Megan Welter

Masters Theses

Multiple System Atrophy (MSA) is a sporadic, neurodegenerative disease that consists of three conditions: autonomic dysfunction, Parkinsonism and cerebellar ataxia. Our lab conducted an Affymetrix global gene expression analysis using pons tissue of MSA patients to determine genes that are differentially expressed when compared to non- MSA controls. This study identified upregulated genes, including the C-X-C chemokine receptor type 4, CXCR4, to which stromal cell-derived factor-I (SDF-1) is the natural ligand. The CXCR4/SDF-1 signaling pair has been sho.wn to play multiple roles in the brain, such as inducing neuronal apoptosis and promoting leukocyte recruitment during inflammation. The MSA cerebellum presents …

A C-Terminus Mitochondrial-Localization Region And Bh3 Domain Of Puma Are Required For Apoptotic Function, Liz A. Merwin

Electronic Thesis and Dissertation Repository

Apoptosis is known to contribute to the loss of neurological function in brain injury and several neurodegenerative diseases. The Bcl-2 family of proteins consist of pro-apoptotic and anti-apoptotic members that interact physically and functionally to regulate apoptosis in a cell type and stimulus specific manner. We have previously demonstrated that the Bcl-2 family member Puma plays a key role in triggering neuronal apoptosis under diverse stress conditions. However, the mechanism by which Puma mediates apoptosis remains unclear. Here we found that Puma contains two domains required for its apoptotic function: the BH3 domain and a region in the c-terminus that …

Targeting The Anaphase Promoting Complex/Cyclosome To Induce Mitotic Arrest In Ovarian Cancer., Douglas John Saforo

College of Arts & Sciences Senior Honors Theses

Taxanes are a class of chemotherapeutic drug that act to disrupt microtubule function and cause mitotic arrest and cell death. These drugs are commonly used for cancer treatment, however their effectiveness is dependent on the presence of a functioning spindle assembly checkpoint (SAC). As a result, it is possible for cancer cells to become resistant to microtubule disrupting drugs by inactivating the SAC. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that acts as the master regulator of cell cycle progression. Inhibition of the APC/C should result in disruption of the cell cycle, resulting in arrest during mitosis …

The Role Of Nucleolin In B-Cell Lymphomas And Fas-Mediated Apoptotic Signaling, Jillian F. Wise

Dissertations & Theses (Open Access)

The death receptor Fas has a key role in mediating homeostasis, elimination of defective cells and more recently implicated in cancer promotion. Many effective anti-cancer therapies depend on Fas-mediated apoptosis to eradicate tumor cells and ineffective Fas-apoptotic signaling is a basis for primary as well as acquired resistance to chemotherapy. We hypothesized that Fas is subjected to direct regulation by inhibitory proteins attained by cancer cells. To screen for potential binding modulators of Fas, we analyzed lymphoma cells for Fas binding proteins. This purification scheme identified high scoring peptides derived from nucleolin, a nuclear protein known to be overexpressed in …

Characterization Of The Apoptotic Functions Of The Hid Hmolog Isolated From Megaselia Scalaris, Shannon Smith

Chancellor’s Honors Program Projects

No abstract provided.

Apoptotic And Epigenetic Induction Of Embryo Failure Following Somatic Cell Nuclear Transfer, Aaron Patrick Davis

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The cloning of domestic species has tremendous potential, as the technology can be used in selective breeding, conservation, and the production of transgenic animals. The technique of cloning involves the transplant of DNA from a cell to a recipient gamete. Following transfer to a surrogate, the cloned embryo may successfully complete development to a live offspring. Despite intensive research, the success rate of cloning remains prohibitively low, and the potential benefits of cloning have not yet been realized. Embryos produced from cloning suffer from high rates of embryo degradation, implantation failure, and abortion. The goal of this dissertation research project …

Oxidative Stress Based Strategies For Enhancing The Efficacy Of Histone Deacetylase Inhibitors (Hdaci), Nilsa Rivera-Del Valle

Dissertations & Theses (Open Access)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the …

Investigating The Interplay Between Protein Kinases And Caspases, Jacob P. Turowec

Electronic Thesis and Dissertation Repository

The balance between cell survival and death is a crucial process in human development and tissue homeostasis, but is also misregulated in disease. In large part, apoptosis is controlled by caspases, a hierarchical series of cysteine aspartic acid proteases that demolish the cell by cleaving key structural and enzymatic proteins, but emerging paradigms have highlighted the ability of kinases to regulate caspase activity. One way in which kinases can control the progression of apoptosis is through phosphorylation of caspase substrates, which acts to prevent caspase cleavage of that target.

In this thesis, we develop new strategies to study this regulatory …

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer Cells To Radiation By Promoting Acidic Ph, Ros, And Jnk Dependent Apoptosis, Melissa Wason

Electronic Theses and Dissertations

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. In this report we determined whether and how cerium oxide nanoparticles (CONPs) sensitize pancreatic cancer cells to RT. CONP pretreatment enhanced radiation-induced reactive oxygen species (ROS) production preferentially in acidic cell-free solutions as well as acidic human pancreatic cancer cells. In acidic environments, CONPs favor the scavenging of superoxide radical over the hydroxyl peroxide resulting in accumulation of the latter whereas in neutral pH CONPs scavenge both. CONP treatment prior to RT markedly potentiated the cancer cell apoptosis both in culture and in tumors and …

Biochemical And Cellular Mechanisms Of Retina And Retinal Pigment Epithelium Apoptosis, Srinivasa Rao Sripathi

Dissertations, Master's Theses and Master's Reports - Open

Oxidative stress, intense light exposure and oxygen imbalances such as hypoxic or hyperoxic conditions perturb mitochondria, nuclear function and further lead to cellular damage of retina and retinal pigment epithelial (RPE) cells. Our major aim is to understand the various biochemical and proteomic events that occur during the progression of retina and RPE cell death. The comprehensive objectives of this dissertation are to understand the functional aspects of protein expression, posttranslational modifications, protein or lipid binding changes, phenotypic, morphological alterations and their regulation during the retina and RPE apoptosis under oxidative stress. The entire study is divided into four chapters …

Effect Of Folate Deficiency And Aging On Mtor Signaling Network In The Liver Of Dna Polymerase B Haploinsufficient Mice, Amanda Lynn Arrabi

Wayne State University Theses

EFFECT OF FOLATE DEFICIENCY AND AGING ON mTOR SIGNALING NETWORK IN THE LIVER OF DNA POLYMERASE B HAPLOINSUFFICIENT MICE

by

AMANDA ARRABI

August 2013

Advisor: Dr. Ahmad R. Heydari

Major: Nutrition and Food Science

Degree: Masters of Science

The interaction between the dietary nutrients and the human genome causes some alterations in the molecular pathways that could significantly impact the development of cancer. The main approach to such concerns is to closely observe how the diet modifies the gene expressions that control several cellular processes in the human body. Folate deficiency (FD) has established an important role in modulating the …

Investigating The Effects Of Bag3 Knockdown On The Cytotoxicity Of The Anticancer Drug Laromustine, Kayla Gross

Honors Theses

Laromustine is a sulfonylhydrazine anticancer prodrug whose cytotoxicity results from the formation of interstrand cross-links caused by the synergistic action of co- generated 2-chloroethylating and carbamoylating species. The cytotoxic activities of Laromustine involve the induction of apoptosis. Described herein is an investigation into this drug’s effects on apoptotic gene expression in HL-60 cells using qRT-PCR. Significant changes in the expression levels of 13 genes were observed, most dramatically in the upregulation of the bcl2-associated athanogene 3 (BAG3) gene. Given the pro-survival role of BAG3 in the cell, this investigation sought to decrease BAG3 mRNA levels in HL-60 cells using transient …

Regulation Of The Tumor Suppresser P53 And Survivin By Ras And Ral Gtpases:Implications For Malignant Transformation, Awet G. Tecleab

USF Tampa Graduate Theses and Dissertations

Abstract

Although the critical role of the small GTPases Ras and Ral in oncogenesis has been well documented, much remains to be investigated about the molecular mechanism by which these GTPases regulate malignant transformation. The work under this thesis made two major contributions to this field. The first is the discovery that K-Ras, RalA and/or RalB are required for the maintenance of the high levels of the anti-apoptotic protein survivin in some human cancer cells, and the second is the demonstration that down regulation of K-Ras, RalA and/or RalB, but not Raf-1 or Akt1/2, stabilizes the tumor suppressor p53 and …

The Role Of Mitochondrial Omi/Htra2 Protease In Protein Quality Control And Mitophagy, Camilla Ambivero

Electronic Theses and Dissertations

Omi/HtrA2 is a mitochondrial serine protease with a dual and opposite function depending on its subcellular localization. Most of the previous studies focused on Omi/HtrA2’s pro-apoptotic function when the protein is released to the cytoplasm. It is becoming apparent that the main function of Omi/HtrA2 is within the mitochondria, where it has a pro-survival role. However, its mechanism is still poorly understood. To this end, we used the yeast two-hybrid system to dissect the Omi/HtrA2 pathway by identifying novel interactors and substrates. Our studies revealed a novel function of Omi/HtrA2 in the regulation of a deubiquitinating (DUB) complex. In addition …