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Oncogene-Dependent Regulation Of Autophagic Flux In Melanoma, Kirsten Anne Meyer White

Biomedical Sciences ETDs

Skin cancer is the one of the most diagnosed cancers in the United States with increasing incidence of 6% every year. In 2015, it is estimated 73,870 new cases of melanoma will be identified and 9,480 individuals will die of their disease. While melanoma only accounts for approximately 2.4% of all cancer related deaths and is the 5th leading diagnosed cancer (US) it is the one of the most common cancers in young adults, age 25-29, particularly for young women. Of particular importance, the mean survival rate of patients diagnosed with metastatic melanoma is six months, with five-year survival rates …

Autophagy And Its Potential Role In Stress And Feed Efficiency Using Avian Lines, Alissa Laura Piekarski

Graduate Theses and Dissertations

Autophagy is a highly conserved cellular mechanism that is responsible for the degradation and recycling of damaged organelles. Recently, autophagy has been involved in critical roles during overall development of the organism and degradation of damaged cellular components. This pathway has witnessed dramatic growth in the last few years and has been extensively studied in yeast and mammals, however, there is a paucity of information in avian (non-mammalian) species. First, we characterized genes involved in the autophagy pathway in male and female Jungle Fowl to determine gender and tissue specific differences. Secondly, tissue and genotype differences in Japanese quail selected …

Leptin Regulates The Expression Of Autophagy-Related Genes In Chickens, Peter Olawale Ishola

Graduate Theses and Dissertations

Autophagy or cellular self-digestion, a lysosomal degradation pathway that is conserved from yeast to human, plays a key role in recycling cellular constituents, including damaged organelles. It also plays a pivotal role in the adaptation of cells to a plethora of distinct stressors including starvation. Autophagy has been extensively studied in mammals and yeast, but little is known in avian species. Thus, the major objective of the present study was to determine the effects of leptin on autophagy-related genes in chicken hypothalamus, muscle and liver. Leptin is an adipocytokine that is mostly produced by white adipose cells in mammals (as …

Coordination Between Autophagy And The Heat Shock Response: Evidence From Exercise In Animals And Humans, Nathan H. Cole

Health, Exercise, and Sports Sciences ETDs

Proteins play a critical role in nearly every biological activity. In consequence, organismal health and homeostasis often hinges on the ability of intracellular regulatory systems to sustain the quality and function of these diverse, structurally complex macromolecules. Correct protein function depends on correct form, and during periods of destabilizing cellular stress, protein quality is managed in part by the heat shock response, which acts to support, isolate, and reform new or damaged proteins, and in part by the autophagic recycling of abnormal proteins, cytotoxic protein aggregates, and terminally damaged organelles. We conducted a pooled analysis of available research in humans …

Novel Mechanism Of Breast Cancer Prevention And Treatment Using Natural Extract Of Pimenta Dioica, Lei Zhang

Open Access Dissertations

Plant-derived dietary compounds have shown potential as chemopreventive and anticancer agents to prolong survival and reduce breast cancer deaths. Lack of specific mechanism of action is the leading concern for adopting these edible compounds as chemopreventive or adjuvant therapeutics against breast and other cancers. The unripe berries of Pimenta Dioica, also called Allspice, are widely used in cuisines worldwide, contain a cornucopia of bioactive compounds with potential therapeutic properties. Limited studies on the potential anticancer compounds present in Allspice prompted us to hypothesize and test potential antiproliferative agents in an aqueous extract of Allspice (AAE). The potential anti-tumor activity of …

Studies On The Roles Of Translationally Recoded Proteins From Cyclooxygenase-1 And Nucleobindin Genes In Autophagy, Jonathan J. Lee

Theses and Dissertations

Advances in next-generation sequencing and ribosomal profiling methods highlight that the proteome is likely orders of magnitude larger than previously thought. This expansion potentially occurs through translational recoding, a process that results in the expression of multiple variations of a protein from a single messenger RNA. Our laboratory demonstrated that cyclooxygenase-3/1b (COX-3/1b), a frameshifted, intron-1-retaining, alternative splice variant from the COX-1 gene, is multiply recoded, which results in the translation of at least seven different COX-3 proteins. Two of the recoded COX-3 proteins that we identified are active prostaglandin synthases and are inhibited by non-steroidal anti-inflammatory drugs (NSAIDs). Here we …

The Roles Of Mist1 And Rab26 In Zymogenic (Chief) Cell Differentiation And Subcellular Organization, Ramon Jin

Arts & Sciences Electronic Theses and Dissertations

Little is known about how differentiating cells reorganize their cellular structure to perform specialized physiological functions. Specifically, exocrine cells like pancreatic acinar and zymogenic chief cells have a highly developed secretory architecture that is rapidly established upon differentiation. What is known in these cells is that the evolutionarily conserved transcription factor MIST1 is required for final maturation. We hypothesized that MIST1 directly regulates specific subcellular components that facilitate functional maturation of secretory cells.

We show that MIST1 binds to conserved CATATG E-boxes to activate transcription of 6 genes, including the small GTPases RAB26 and RAB3D. We next demonstrate that RAB26 …

Gcn5l1 Functions As A Mitochondrial Acetyltransferase That Regulates Mitophagy, Bradley Roy Webster

Biomedical Sciences ETDs

Caloric restriction (CR) increases lifespan and promotes both longevity and €˜healthy-aging. CR's benefits are dependent in part on NAD-dependent deacetylases known as sirtuins. NAD levels increase with CR promoting sirtuin-mediated deacetylation of lysine residues. Humans express seven sirtuin isoforms that localize to specific sub-cellular compartments. Sirtuins and acetylation affect numerous cellular processes including mitochondrial function. Sirt3 is the major mitochondrial deacetylase and regulates mitochondrial function namely ATP levels, oxidative stress and metabolism. Given the importance of mitochondrial acetylation and Sirt3, we hypothesized the existence of a mitochondrial-localized acetyltransferase that 1) localizes to the mitochondria; 2) has an acetyltransferase domain; and …

The Role Of Autophagy In The Sensitivity Of Osteosarcoma Cells To Gemcitabine Treatment, Janice M. Santiago-O'Farrill

Dissertations & Theses (Open Access)

Despite treatment improvement for osteosarcoma (OS), overall survival has remained unchanged in the last 20 years. Pulmonary metastasis continues to be the main cause of death; novel therapeutic strategies are urgently needed to improve the survival rate of these patients. Previous data in our laboratory has demonstrated that aerosol gemcitabine (GCB) treatment has a significant therapeutic effect on metastatic OS. However, treatment efficacy is decreased due to acquired resistance by a population of tumor cells that fails to respond to treatment. Recent studies have implicated autophagy as a resistance mechanism in various types of cancer. The purpose of this study …

Rab Proteins And Alzheimer's: A Current Review Of Their Involvement In Amyloid Beta Generation With Focus On Rab10 Expression In N2a-695 Cells, Ivan Arano Rodriguez

Theses and Dissertations

This thesis work describes the role of Rab proteins in amyloid processing and clearance in different cell pathways. It also describes an experimental approach used to analyze the expression effects of Rab10 in amyloid beta production. Since the main theory behind neurodegeneration in Alzheimer's disease claims that high levels of amyloid beta 42 (Aβ42) molecules trigger widespread neuronal death, control of Aβ42 has been a main target in Alzheimer's disease research. In addition, several studies show increased levels of particular Rab proteins in Alzheimer's pathogenesis. However, no review consolidates current findings in neurodegeneration of Alzheimer's with Rab protein dysfunction. The …

A Protective Role Of Autophagy In A Drosophila Model Of Friedreich's Ataxia (Frda), Luan Wang

Wayne State University Dissertations

Friedreich’s ataxia (FRDA) is an inherited autosomal recessive neurodegenerative disease. It affects 1 in every 50,000 people in central Europe and North America. FRDA is caused by deficiency of Frataxin, an essential mitochondrial iron chaperone protein, and the associated oxidative stress damages. Autophagy, a housekeeping process responsible for the bulk degradation and turnover of long half-life proteins and organelles, is featured by the formation of double-membrane vacuoles and lysosomal degradation. Previous researches indicate that Danon’s disease, the inherited neural disorder disease that shares similar symptoms with FRDA, is due to the malfunction of autophagy. Based on this, we raise the …

Targeting Autophagy In Multiple Myeloma, Yun Dai

Theses and Dissertations

Apoptosis (Type I) and autophagy (Type II) represent two major forms of programmed cell death. Numerous anticancer agents employed in standard chemotherapy or novel targeted therapy induce both apoptosis and autophagy. Of note, a cytoprotective autophagic response often counteracts apoptosis triggered by such agents, potentially contributing to drug-resistance. Mechanistically, autophagy and apoptosis share molecular regulatory mechanisms primarily governed by the Bcl-2 family proteins. However, since autophagy acts as the double-edge sword in cancer, whether autophagy should be inhibited or activated in cancer treatment remains the subject of debate. Here we report a) a novel autophagy-targeted strategy that targeting the adaptor …

Cardiolipin Regulates Mitophagy Through The Pkc Pathway, Zheni Shen

Wayne State University Dissertations

Cardiolipin (CL), the signature phospholipid of mitochondrial membranes, is important for cardiovascular health. Perturbation of CL metabolism is implicated in cardiovascular disease (CVD). The link between CL and CVD may be explained by the physiological roles of CL in pathways that are cardioprotective, such as autophagy/mitophagy and the mitogen-activated protein kinase (MAPK) pathways. My dissertation work focuses on elucidating how CL influences mitophagy and MAPK pathways.

crd1Δ was synthetically lethal/sick with the general autophagy mutants atg8Δ, atg18Δ and mitophagy mutant atg32Δ, suggesting that autophagy/mitophagy may be deficient in cells lacking CL. Microscopic examination of mitophagy revealed decreased translocation of GFP-tagged …

Relationship Between Autophagy, Senescence, And Dna Damage In Radiation Sensitization By Parp Inhibition, Moureq Alotaibi

Theses and Dissertations

Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In …

Potential Role Of Protein Kinase Cbeta In High Fat Diet-Induced Adipose Dysfunction By Regulating Autophagy Levels, Neil Mehta

Williams Honors College, Honors Research Projects

Obesity is the most common nutritional disorder in the United States and worldwide. Public health efforts and other anti-obesity measures clearly have not controlled the obesity epidemic. There is a great need to understand the pathogenic mechanisms underlying fat accumulation. Research of the past decade supports a prominent role for diet-induced adipose tissue dysfunction in the development and/or progression of obesity and associated insulin resistance. Potential mechanisms for the development of adipose tissue dysfunction include ectopic (visceral) fat accumulation, genetic factors, and alterations in autophagy and inflammatory processes. However, the molecular mechanisms linking dietary fat intake with alterations in adipose …

Linking Adiponectin And Autophagy In The Regulation Of Breast Cancer Metastatic Potential, Emily Libby

All ETDs from UAB

Curative approaches for metastatic breast cancer remain elusive. Adiponectin is the most abundant of the adipocyte-secreted adipokines, and there is recent interest in development of adiponectin-based therapies for this disease. Yet, while multiple epidemiological studies have indicated that low levels of circulating plasma adiponectin portend poorer prognosis, recent work has reported that elevated adiponectin expression in breast tissue correlates with advanced disease. Further, isoform-specific roles of this molecule are not well understood. Thus, the overarching purpose of this work was to elucidate how adiponectin isoforms contribute to the microenvironmental regulation of the early steps of breast cancer metastasis. We show …

Changes In Gene Expression During Nitrogen Starvation Are Mediated By Targeted Degradation Of Translation And Mrna Decay Factors In Saccharomyces Cerevisiae, Shane Patrick Kelly

All ETDs from UAB

Autophagy is the cellular mechanism of recruitment and decay of cytoplasmic molecules, proteins, and organelles that are obsolete for a particular growth condition. Autophagic degradation is distinct from proteasomal degradation by the formation of a de-novo double membrane which engulfs its cargo to be delivered for degradation to the yeast vacuole. Once thought to be only a general phenomenon of bulk decay, several autophagic pathways have demonstrated selectivity. In the following work we show that during nitrogen starvation (a potent inducer of autophagy) in the yeast Saccharomyces cerevisiae, a subset of translation factors are degraded selectively and rapidly. We go …

Nucleolar Proteins Are Essential For Ribosome Biogenesis And Nuclear Homeostasis In Drosophila Melanogaster, Yubo Wang

LSU Doctoral Dissertations

Four nucleostemin-like proteins (NS1-4) were identified previously in Drosophila melanogaster. NS1 and NS2 are nucleolar proteins, while NS3 and NS4 are cytoplasmic. Here we show that NS2 is homologous to the human nucleostemin-like protein, Ngp1, and that endogenous NS2 and exogenous GFP-NS2 enriches within peripheral regions of nucleoli in larval polyploid midgut cells. Like NS1, depletion of NS2 in midgut cells blocked the release of the 60S ribosomal subunit as detected by the accumulation GFP-RpL11 within nucleoli, and this likely led to a general loss of 60S subunit proteins as shown by immunoblot analyses. At the ultrastructural level, nucleoli in …

Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson

All ETDs from UAB

Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …