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C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein Dec 2013

C-Jun N-Terminal Kinases Regulate Adenovirus-Mediated Autophagy And Antigen Presentation, Sarah R. Klein

UT GSBS Dissertations and Theses (Open Access)

Targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for oncolysis, but the molecular regulation of autophagy in infected cells remains under investigation. Our data suggested the canonical pathway regulating starvation-induced autophagy was not implemented in adenovirus-induced autophagy; however, adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) that was essential for autophagy. Adenoviral replication within the host cell elicited JNK pathway activation leading to B cell lymphoma-2 (Bcl-2) phosphorylation. JNK-dependent Bcl-2 phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy ...


A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang Sep 2013

A Novel Autophagy Regulatory Mechanism That Functions During Programmed Cell Death: A Dissertation, Tsun-Kai Chang

GSBS Dissertations and Theses

Autophagy is a cellular process that delivers cytoplasmic materials for degradation by the lysosomes. Autophagy-related (Atg) genes were identified in yeast genetic screens for vehicle formation under stress conditions, and Atg genes are conserved from yeast to human. When cells or animals are under stress, autophagy is induced and Atg8 (LC3 in mammal) is activated by E1 activating enzyme Atg7. Atg8-containing membranes form and surround cargos, close and mature to become the autophagosomes. Autophagosomes fuse with lysosomes, and cargos are degraded by lysosomal enzymes to sustain cell viability. Therefore, autophagy is most frequently considered to function in cell survival. Whether ...


Features Of Dormancy In Metastatic Ovarian Cancer Cells, Rohann Jm Correa Jul 2013

Features Of Dormancy In Metastatic Ovarian Cancer Cells, Rohann Jm Correa

Electronic Thesis and Dissertation Repository

The most prevalent subtype of ovarian cancer – high-grade serous (HGS) carcinoma – is also the most lethal, since the majority of cases are characterized by advanced-stage (metastatic) presentation. Metastasis of this cancer proceeds by an intra-peritoneal route, involving detachment of cells from the primary tumour and dissemination throughout the peritoneal cavity as multicellular aggregates, or spheroids. Herein, we demonstrate that HGS patient-derived tumour cells cultured to form in vitro spheroids exhibit features of cancer dormancy, a cellular state known to promote therapeutic resistance and disease recurrence. We discovered that upon spheroid formation, cells became non-proliferative, exhibiting a cell cycle profile and ...


Dual Role Of Oxidative Stress In Head And Neck Cancer Chemotherapy: Cytotoxicity And Pro-Survival Autophagy, Arya Sobhakumari Jul 2013

Dual Role Of Oxidative Stress In Head And Neck Cancer Chemotherapy: Cytotoxicity And Pro-Survival Autophagy, Arya Sobhakumari

Theses and Dissertations

Cancer cells are believed to exist in a condition of metabolic oxidative stress compared to normal cells because of inherent mitochondrial dysfunction. Cancer cells up regulate antioxidant defense mechanisms to combat the toxic effect of reactive oxygen species (ROS). Many anticancer agents block ROS detoxification mechanisms and utilize oxidative stress to cause cytotoxicity to cancer cells. However, ROS also up-regulate many pro-survival signaling pathways that may mediate resistance to chemotherapy. I hypothesize that ROS induces both cytotoxicity and pro-survival mechanisms in cells treated with chemotherapeutic agents such as the EGFR inhibitor erlotinib. This thesis explores how oxidative stress may induce ...


Targeting Histone Deacetylases (Hdac) For The Treatment Of Soft Tissue Sarcoma, Gonzalo Lopez May 2013

Targeting Histone Deacetylases (Hdac) For The Treatment Of Soft Tissue Sarcoma, Gonzalo Lopez

UT GSBS Dissertations and Theses (Open Access)

Targeting Histone deacetylases (HDAC) for the treatment of genetically complex soft tissue sarcoma

Histone deactylase inhibitors (HDACi) are a new class of anticancer therapeutics; however, little is known about HDACi or the individual contribution of HDAC isoform activity in soft tissue sarcoma (STS). We investigated the potential efficacy of HDACi as monotherapy and in combination with chemotherapy in a panel of genetically complex STS. We found that HDACi combined with chemotherapy significantly induced anti-STS effects in vitro and in vivo. We then focused our study of HDACi in malignant peripheral nerve sheath tumor (MPNST), a subtype of highly aggressive, therapeutically ...


Molecular Basis Of Nod1 And Nod2 Signaling, Aaron Martin Ver Heul May 2013

Molecular Basis Of Nod1 And Nod2 Signaling, Aaron Martin Ver Heul

Theses and Dissertations

NOD1 and NOD2 (nucleotide-binding oligomerization domain-containing proteins 1 and 2) are related innate immune receptors responsible for initiating a response to bacterial infection. They belong to a class of receptors known as Pattern Recognition Receptors (PRRs), which are germline encoded immune receptors that mediate various innate immune responses. These receptors recognize conserved microbial motifs known as Pathogen-Associated Molecular Patterns (PAMPs). The PRR-PAMP paradigm forms the bedrock of how innate immunity is understood today. As two of the first intracellular PRRs discovered, NOD1 and NOD2 came to define an entire subclass of PRRs, the NOD-like receptors (NLRs). PRRs relay their signals ...


Role Of Autophagy In Post-Mitotic Midbody Fate And Function: A Dissertation, Tse-Chun Kuo Mar 2013

Role Of Autophagy In Post-Mitotic Midbody Fate And Function: A Dissertation, Tse-Chun Kuo

GSBS Dissertations and Theses

The midbody (MB) is a proteinaceous complex formed between the two daughter cells during cell division and is required for the final cell separation event in late cytokinesis. After cell division, the post-mitotic midbody, or midbody derivative (MBd), can be retained and accumulated in a subpopulation of cancer cells and stem cells, but not in normal diploid differentiated cells. However, the mechanisms by which MBds accumulate and function are unclear. Based on this, I hypothesize that the MBd is degraded by autophagy after cell division in normal diploid differentiated cells, whereas non-differentiated cells have low autophagic ...


The Interplay Between Lewy Body-Like Alpha-Synuclein Aggregates Nd Protein Degradation Pathways In Cell-Based Model Of Parkinson's Disease, Selcuk Aski Tanik Jan 2013

The Interplay Between Lewy Body-Like Alpha-Synuclein Aggregates Nd Protein Degradation Pathways In Cell-Based Model Of Parkinson's Disease, Selcuk Aski Tanik

Publicly Accessible Penn Dissertations

Cytoplasmic alpha-synuclein (a-syn) aggregates, including Lewy bodies (LBs), are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson's disease (PD). Activation of intracellular protein degradation pathways (Pdps) to eliminate these aggregates has been proposed as a therapeutic approach for PD and other synucleinopathies, but the interplay between LB-like a-syn aggregates and Pdps is not completely understood. Here, we investigate this interplay by utilizing a recently developed cellular model in which intracellular LB-like a-syn inclusions accumulate after delivery of pre-formed a-syn fibrils (Pffs) into a-syn-expressing HEK293 cells or cultured primary neurons. This thesis describes the interplay between LB-like ...


Drug Resistance Mechanisms To Gamma-Secretase Inhibitors In Human Colon Cancer Cells, Cindy R. Timme Jan 2013

Drug Resistance Mechanisms To Gamma-Secretase Inhibitors In Human Colon Cancer Cells, Cindy R. Timme

Graduate Theses and Dissertations

Colorectal cancer is the third leading cause of cancer-related mortality. Much progress has been achieved in combating this disease with surgical resection and chemotherapy in combination with targeted drugs. However, most metastatic patients develop drug resistance so new modalities of treatment are needed.

Notch signaling plays a vital role in intestinal homeostasis, self-renewal, and cell fate decisions during post-development and is activated in colorectal adenocarcinomas. Under debate is its role in carcinomas and metastatic disease. In theory, blocking Notch activation using gamma-secretase inhibitors (GSIs) may show efficacy alone or in combination with chemotherapy in the treatment of colon cancer.

In ...


Development Of Immunotherapeutic Approaches To Achieve Xenophagy In Macrophages Infected With Rhodococcus Equi, Mahesh Bhandari Jan 2013

Development Of Immunotherapeutic Approaches To Achieve Xenophagy In Macrophages Infected With Rhodococcus Equi, Mahesh Bhandari

Graduate Theses and Dissertations

Macrophages are the host cells for Rhodococcus equi. Activation of FcγRI can induce phagocytosis, antigen presentation, cytokine production, antibody-dependent cell mediated cytotoxicity, reactive oxygen species (ROS) production, and induction of autophagy machinery in macrophages. Here we observe enhanced macrophage bactericidal activity against intracellular R. equi concurrent with superoxide production and induction of autophagy. Following ligation of IFN-γ, TLR4 and FcγRI receptors, murine bone marrow-derived macrophages, equine pulmonary-alveolar macrophages and monocyte-derived macrophages were tested for superoxide production, induction of autophagy and bacterial load through multispectral imaging flow cytometry, western blot and confocal microscopy. Results show that ligation of these receptors alone ...


An Evolutionarily Conserved Role For Autophagy In Antiviral Defense, Ryan Moy Jan 2013

An Evolutionarily Conserved Role For Autophagy In Antiviral Defense, Ryan Moy

Publicly Accessible Penn Dissertations

Innate immunity is the first line of defense against viral infection and depends on the use of germline-encoded pattern recognition receptors (PRRs) that detect pathogen-associated molecular patterns (PAMPs). Virus recognition subsequently triggers an assortment of effector responses that are critical for clearing the invading pathogen. Among known antiviral pathways, autophagy, a biological process that mediates the degradation of cytoplasmic components, may be one of the most ancient. We previously demonstrated that autophagy is essential for resistance to the Rhabdovirus Vesicular stomatitis virus (VSV) in flies. However, the mechanism by which autophagy is triggered during VSV infection remained unclear. Through a ...


Evading Innate And Adaptive Immunity During Adenovirus Cell Entry, Shauna Marvin Jan 2013

Evading Innate And Adaptive Immunity During Adenovirus Cell Entry, Shauna Marvin

Dissertations

Adenovirus (Ad), a non-enveloped, dsDNA virus, enters cells via clathrin-mediated endocytosis. For viral genome delivery to the nucleus, Ad must penetrate endosomal membranes to create defects sufficient for the passage of the 90 nm diameter capsid across cell membranes. Recent observations suggest that adenovirus type 5 (Ad5) capsid uncoating occurs at the cell surface upon binding to both the coxsackievirus and adenovirus receptor and αv integrins. This uncoating event leads to the exposure of the capsid membrane lytic protein VI. Using the cytosolic protein galectin-3 (gal3) as a marker of membrane rupture, we demonstrate that Ad5 membrane rupture occurs ...