Cell and Developmental Biology Commons^™

Mdm2-Mediated Degradation Of Sirt6 Phosphorylated By Akt1 Promotes Tumorigenesis And Trastuzumab Resistance In Breast Cancer, Umadevi Thirumurthi

Dissertations and Theses (Open Access)

Sirtuin6 (SIRT6) is one of the members of the Sirtuin family and functions as a longevity assurance gene by promoting genomic stability. It also regulates various cancer-associated pathways and was recently established as a bonafide tumor suppressor in colon cancer. This suggests that SIRT6 is an attractive target for pharmacological activation in cancer treatment, and hence, identification of potential regulators of SIRT6 would be an important and critical contribution towards cancer treatment. Here, we show that AKT1 phosphorylates SIRT6 at Ser³³⁸ and induces MDM2-SIRT6 interaction, priming SIRT6 for degradation via the MDM2-dependent ubiquitin-proteasome pathway. Blocking SIRT6 Ser³³⁸ phosphorylation …

Jab1 Negatively Regulates Pten And Promotes Resistance To Trastuzumab In Her2-Positive Breast Cancer, Thuy T. Vu

Dissertations and Theses (Open Access)

HER2-positive breast cancer, which is characterized by the over-expression of the HER2 onco-protein, accounts for approximately 20% of all breast cancer cases. Trastuzumab (Herceptin), the first targeted therapy approved for HER2-positive disease, potently prevents the activation of signaling pathways downstream of HER2 and significantly improves patients’ outcomes. However, resistance to trastuzumab is inevitable; such resistance can occur through reduced expression of PTEN protein.

Jab1 is over-expressed in 50% of primary cancers and 90% of metastatic tumors. Our lab previously showed that depletion of Jab1 in combination with trastuzumab treatment up-regulated PTEN in mouse xenografts refractory to trastuzumab. PTEN was not …

Epidermal Growth Factor Receptor Induces Fyn Expression Via Up-Regulation Of P47phox In Glioblastoma Multiforme, Blake P. Johnson

Dissertations and Theses (Open Access)

Src family kinases (SFKs) are commonly over-expressed and/or activated in glioblastoma multiforme (GBM), where they serve as key mediators of GBM cell proliferation, survival, invasion and angiogenesis. Mechanisms of allosteric SFK activation are well described; however, the SFK Fyn is commonly up-regulated at the mRNA level in multiple human cancers, including GBM, where the mode of increased expression is poorly understood. Since activating mutations in the epidermal growth factor receptor (EGFR) are commonly occurring in GBM, we examined whether EGFR could induce Fyn expression. Here, we found that wild-type EGFR, and to a greater extent hyper-activating EGFR mutants, EGFRΔIII and …

Targeting Cox-2 And Rank In Aggressive Breast Cancers: Inflammatory Breast Cancer And Triple-Negative Breast Cancer, Monica Elizabeth Reyes

Dissertations and Theses (Open Access)

Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are two highly aggressive breast cancer subtypes associated with a poor outcome. Despite sensitivity to current treatment, these breast cancers subtypes have a high recurrence rate and proclivity to metastasize early. The aggressiveness of IBC and TNBC have been linked to CSCs and epithelial to mesenchymal transition (EMT), which are critical features of breast cancer progression and metastasis. The clinical challenge faced in the treatment of IBC and TNBC is finding a treatment strategy to target the cancer stem-like (CSC) population to block metastasis. Cyclooxygenase-2 (COX-2) and receptor activator of nuclear …

Investigation Of Nuclear And Cytoplasmic Functions Of The Dlipin Protein Of Drosophila Melanogaster, Qiuyu Chen

Graduate Theses and Dissertations

Lipin family proteins are highly conserved proteins present in species ranging from mammals to yeast. Lipin 1, the first Lipin gene identified in fatty liver dystrophy (fld) mutant mice, encodes the bifunctional protein Lipin 1, which can serve as an Mg2+-dependent phosphatidic acid phosphatase (PAP) and transcriptional co-regulator. dLipin, the single Lipin ortholog of Drosophila melanogaster, is required in triglyceride synthesis and fat body development. To study the transcriptional co-regulator activity of dLipin, nuclear receptors were screened to find receptors that interact with dLipin. The genetic interaction data indicated that Drosophila hepatic nuclear receptor 4 (HNF4) was a promising candidate …

Managing Devil Facial Tumour Disease In Tasmanian Devils (Sarcophilus Harrisii): An Investigation Of Heat Shock Proteins As Potential Vaccine Adjuvants, Monika Payerhin

Independent Study Project (ISP) Collection

The world’s largest carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), is facing extinction from a deadly, highly communicable cancer that has already decimated over 85% of devil populations in the wild: devil facial tumour disease (DFTD). DFTD cells effectively evade recognition by the immune system, and every devil that contracts the disease dies from it. Many attempts have been made at developing a vaccine that could help save this now-threatened species. Heat shock proteins have been linked to enhanced immune recognition of pathogens, making them potential candidates for acting as adjuvants to such a vaccine against DFTD. In this study, …

Induction Of Differentiation Of Dental Pulp-Derived Mesenchymal Stem Cells (Dpsc), Aubrey Young

UNLV Theses, Dissertations, Professional Papers, and Capstones

Mesenchymal stem cells are derived from a variety of human tissues and are being bioengineered and studied for possible uses in the advancement of medicine. Recent efforts are being focused on Dental Pulp Stem Cells (DPSC's) due to the accessibility of this tissue. Many factors influence DPSC quality and quantity, including the specific methods used to isolate, collect, concentrate, and store these isolates once they are removed. Ancillary factors, such as the choice of media, the selection of early versus late passage cells, and cryopreservation techniques may also influence the differentiation potential and proliferative capacity of DPSC isolates.

The objective …

Extent Of Cysteine Modification Of Snap-25 In Vitro, Alex Mcgregor Dabell

Theses and Dissertations

Exocytosis, the fusion of a vesicle to a cellular membrane, involves a protein named SNAP-25. This protein, containing two alpha helices connected with a linker region, is localized to the cell membrane via palmitic acids attached to the cysteine residues of its linker region in a process called palmitoylation. Are cysteine residues of the SNAP-25 linker region palmitoylated in an ordered manner and to a particular extent? The answer to this question may give insight into the regulated nature of exocytosis. While it is generally accepted that SNAP-25 must be palmitoylated in order to perform its exocytotic functions, the details …

Alcohol Modulation Of Dopamine Release, Nathan Dan Schilaty

Theses and Dissertations

The mesolimbic dopamine (DA) system projects from the ventral tegmental area (VTA) to structures associated with the limbic system, primarily the nucleus accumbens (NAc). This system has been implicated in the rewarding effects of drugs of abuse. Many drugs of abuse act in the VTA, the NAc, or both. Dopamine neurons in the VTA that project to the NAc, and the GABA neurons that inhibit DA neurons locally in the VTA or project to the NAc, play an important role in mediating addiction to various drugs of abuse, in particular alcohol. There is a growing body of evidence of co-dependence …

Aspartate Β-Hydroxylase Expession Promotes A Malignant Pancreatic Cellular Phenotype, Xiaoqun Dong, Qiushi Lin, Arihiro Aihara, Gregory Gabriel

Faculty Articles

Pancreatic cancer (PC) is one of the leading causes of cancer related deaths due to aggressive progression and metastatic spread. Aspartate β-hydroxylase (ASPH), a cell surface protein that catalyzes the hydroxylation of epidermal growth factor (EGF)-like repeats in Notch receptors and ligands, is highly overexpressed in PC. ASPH upregulation confers a malignant phenotype characterized by enhanced cell proliferation, migration, invasion and colony formation in vitro as well as PC tumor growth in vivo. The transforming properties of ASPH depend on enzymatic activity. ASPH links PC growth factor signaling cascades to Notch activation. A small molecule inhibitor of β-hydroxylase activity was …

Structure-Based Network Analysis Of Activation Mechanisms In The Erbb Family Of Receptor Tyrosine Kinases: The Regulatory Spine Residues Are Global Mediators Of Structural Stability And Allosteric Interactions, Kevin A. James, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

The ErbB protein tyrosine kinases are among the most important cell signaling families and mutation-induced modulation of their activity is associated with diverse functions in biological networks and human disease. We have combined molecular dynamics simulations of the ErbB kinases with the protein structure network modeling to characterize the reorganization of the residue interaction networks during conformational equilibrium changes in the normal and oncogenic forms. Structural stability and network analyses have identified local communities integrated around high centrality sites that correspond to the regulatory spine residues. This analysis has provided a quantitative insight to the mechanism of mutation-induced ‘‘superacceptor’’ activity …

Tributyltin Alters Secretion Of Interleukin 1 Beta From Human Immune Cells, Shyretha Brown, Margaret Whalen

Chemistry Faculty Research

Tributyltin (TBT) has been used as a biocide in industrial applications such as wood preservation, antifouling paint and antifungal agents. Owing to its many uses, it contaminates the environment and has been found in human blood samples. Interleukin-1 beta (IL-1β) is a pro-inflammatory cytokine that promotes cell growth, tissue repair and immune response regulation. Produced predominately by both monocytes and macrophages, IL-1β appears to increase the invasiveness of certain tumors. This study shows that TBT modifies the secretion of IL-1β from increasingly reconstituted preparations of human immune cells. IL-1β secretion was examined after 24-, 48-h or 6-day exposures to TBT …

A Ventilator Strategy Combining Low Tidal Volume Ventilation, Recruitment Maneuvers, And High Positive End-Expiratory Pressure Does Not Increase Sedative, Opioid, Or Neuromuscular Blocker Use In Adults With Acute Respiratory Distress Syndrome And May Improve Patient Comfort, Sangeeta Mehta, Deborah J. Cook, Yoanna Skrobik, John Muscedere

Anatomy and Cell Biology Publications

Background: The Lung Open Ventilation Study (LOV Study) compared a low tidal volume strategy with an experimental strategy combining low tidal volume, lung recruitment maneuvers, and higher plateau and positive end-expiratory pressures (PEEP) in adults with acute respiratory distress syndrome (ARDS). Herein, we compared sedative, opioid, and neuromuscular blocker (NMB) use among patients managed with the intervention and control strategies and clinicians' assessment of comfort in both groups. Methods: This was an observational substudy of the LOV Study, a randomized trial conducted in 30 intensive care units in Canada, Australia, and Saudi Arabia. In 16 centers, we recorded daily doses …

Peptide Arrays For Detecting Naphthenic Acids In Oil Sands Process Affected Water, Kamaljit Kaur, Subir Bhattacharjee, Rajesh G. Pillai, Sahar Ahmed, Sarfuddin Azmi

Pharmacy Faculty Articles and Research

Naphthenic acids (NAs) are water-soluble components of petroleum. The characterization and quantification of NAs by analytical methods have proved quite challenging, whilst the toxic effects of these water-soluble compounds on a variety of organisms adversely affecting reproduction and steroid production is becoming apparent. In this study, we report a fluorescence-based competitive binding method for rapid sensing of the presence of NAs using cellulosic peptide array strips as sensors. The peptide array was designed from sequences derived from the estrogen receptor (ER). Several of these peptides were able to detect the presence of NAs at low micromolar (∼5 mg L^{−1 …}

Novel Biomarkers Can Be Used As Targets To Combat Cancer, Harini Krishnan

Graduate School of Biomedical Sciences Theses and Dissertations

Cancer kills almost 8 million people per year worldwide. Therefore, about 13 people die from cancer every minute. Clearly, current cancer treatments are not completely effective. Moreover, many chemotherapeutic reagents are not very specific for cancer cells.

These agents attack rapidly dividing cells, including a wide array of normal cells, in addition to cancer cells, in the body. This lack of specificity can cause collateral damage and significant side effects in patients. More targeted therapies are needed to successfully combat cancer. Specific cancer biomarkers need to identified and characterized in order to develop better targeted anti-cancer drugs.

Tumor cells can …

Neural Stem Cells As A Model To Study Huntington’S Disease, Rawan Bakhsh

Dissertations, Masters Theses, Capstones, and Culminating Projects

Huntington’s disease (HD) is a heritable neurodegenerative disorder that affects muscle coordination and diminishes cognitive abilities, by affecting the medium spiny neurons in the brain. In HD patients, neurons are damaged and destroyed because of the toxicity of the mutant Huntington protein (mHtt). The mechanism of how mHtt protein affects the neurons is unknown. In this study we explored the effects of mHtt expression by looking at changes in huntingtin localization, changes in the expression and co-localization of related proteins and differences in cell morphology. We examine how this expression affects the cytoskeletal structures using neural stem cells Q7 (wild …

Majority Of Cells Lining The Walls Of The 3rd Ventricle In The Adult Rat Brain Are Not Neural Progenitor Cells, C. Hasken, S. Vermilyea, M. Hendrickson, R. Kalil

Annual Student Research Poster Session

No abstract provided.

Intercellular Cooperation And Competition In Brain Cancers: Lessons From Drosophila And Human Studies, Indrayani Waghmare, Austin Roebke, Mutsuko Minata, Madhuri Kango-Singh, Ichiro Nakano

Biology Faculty Publications

Glioblastoma (GBM) is a primary brain cancer with an extremely poor prognosis. GBM tumors contain heterogeneous cellular components, including a small subpopulation of tumor cells termed glioma stem cells (GSCs). GSCs are characterized as chemotherapy- and radiotherapy-resistant cells with prominent tumorigenic ability. Studies in Drosophila cancer models demonstrated that interclonal cooperation and signaling from apoptotic clones provokes aggressive growth of neighboring tumorigenic clones, via compensatory proliferation or apoptosis induced proliferation. Mechanistically, these aggressive tumors depend on activation of Jun-N-terminal kinase (upstream of c-JUN), and Drosophila Wnt (Wg) in the apoptotic clones. Consistent with these nonmammalian studies, data from several mammalian …

Brominated Flame Retardants, Tetrabromobisphenol A And Hexabromocyclododecane, Activate Mitogen-Activated Protein Kinases (Mapks) In Human Natural Killer Cells, Anita Cato, Lindsay Celada, Esther Caroline Kibakaya, Nadia Simmons, Margaret M. Whalen

Chemistry Faculty Research

Natural killer (NK) cells provide a vital surveillance against virally infected cells, tumor cells, and antibody-coated cells through the release of cytolytic mediators and gamma interferon (IFN-γ). Hexabromocyclododecane (HBCD) is a brominated flame retardant used primarily in expanded (EPS) and extruded (XPS) polystyrene foams for thermal insulation in the building and construction industry. Tetrabromobisphenol A (TBBPA) is used both as a reactive and an additive flame retardant in a variety of materials. HBCD and TBBPA contaminate the environment and are found in human blood samples. In previous studies, we have shown that other environmental contaminants, such as the dibutyltin (DBT) …

Novel Therapeutic Strategies In Lung Cancer, Courtney A. Kurtyka

USF Tampa Graduate Theses and Dissertations

Lung cancer is the leading cause of cancer-related death and the second most diagnosed cancer in the United States. Unfortunately, many patients either do not have any common mutations for which there are already targetable agents, or they eventually become resistant to these compounds. As such, there is a high demand for new, effective methods of treating this disease as well as predicting patient prognosis and potential benefit from chemotherapy. In this work, numerous strategies for treating lung cancer are explored.

The first method described here is through the use of a pan-early 2 factor (E2F) inhibitor, HLM006474, which is …

Astrocyte-Specific Regulation Of Hmecp2 Expression In Drosophila, David Hess-Homeier, Chia-Yu Fan, Tarun Gupta, Ann-Shyn Chiang, Sarah J. Certel

Biological Sciences Faculty Publications

Alterations in the expression of Methyl-CpG-binding protein 2 (MeCP2) either by mutations or gene duplication leads to a wide spectrum of neurodevelopmental disorders including Rett Syndrome and MeCP2 duplication disorder. Common features of Rett Syndrome (RTT), MeCP2 duplication disorder, and neuropsychiatric disorders indicate that even moderate changes in MeCP2 protein levels result in functional and structural cell abnormalities. In this study, we investigated two areas of MeCP2 pathophysiology using Drosophila as a model system: the effects of MeCP2 glial gain-of-function activity on circuits controlling sleep behavior, and the cell-type specific regulation of MeCP2 expression. In this study, we first examined …

The Evolution Of Prostate Cancer Therapy: Targeting The Androgen Receptor (Ar), Jeanny B. Aragon-Ching

Medicine Faculty Publications

No abstract provided.

Induction Of Acute Lung Inflammation In Mice With Hemorrhagic Shock And Resuscitation: Role Of Hmgb1, Raymond L. C. Kao, Xuemei Xu, Anargyros Xenocostas, Neil Parry, Tina Mele, Claudio M. Martin, Tao Rui

Anatomy and Cell Biology Publications

Background: Hemorrhagic shock and resuscitation (HS/R) can induce multiple organ failure which is associated with high mortality. The lung is an organ commonly affected by the HS/R. Acute lung injury is a major cause of dysfunction in other organ systems. The objective of this study is to test the hypothesis that HS/R causes increased gut permeability which results in induction of high mobility group box1 protein (HMGB1) and further leads to the development of acute lung inflammation. Materials and methods: A mouse model of HS/R was employed in this study. Gut permeability and bacterial translocation were assessed with circulating FD4 …

Genetic Analysis Of Ton2 Dependent Processes In Microtubule Organization In Arabidopsis Thaliana, Samantha Nicole Atkinson

Theses and Dissertations

Microtubules carry out many functions within the cell. They're used during mitosis and meiosis to move chromosomes to opposite sides of the cell so that cell division can occur. They're also used as structural support for the cell and are involved in establishing the cell shape. Microtubules are also able to reorient from a longitudinal orientation to a transverse orientation in response to gibberellic acid and auxin (two hormones that are involved in cell elongation). The mechanism for how this reorientation occurs is unknown. The TONNEAU2 (TON2) protein is necessary for proper microtubule organization. We looked at how TON2 affects …

Asynchronous Remodeling Is A Driver Of Failed Regeneration In Duchenne Muscular Dystrophy, Sherry Dadgar, Zuyi Wang, Helen Johnston, Akanchha Kesari, Kanneboyina Nagaraju, Yi-Wen Chen, D. Ashley Hill, Terence A. Partridge, Robert J. Freishtat, Javad Nazarian, Jianhua Xuan, Yue Wang, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β-centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are …

Neural Transcription Factors: From Embryos To Neural Stem Cells, Hyun-Kyung Lee, Hyun-Shik Lee, Sally Ann Moody

Anatomy and Regenerative Biology Faculty Publications

The early steps of neural development in the vertebrate embryo are regulated by sets of transcription factors that control the induction of proliferative, pluripotent neural precursors, the expansion of neural plate stem cells, and their transition to differentiating neural progenitors. These early events are critical for producing a pool of multipotent cells capable of giving rise to the multitude of neurons and glia that form the central nervous system. In this review we summarize findings from gain- and loss-of-function studies in embryos that detail the gene regulatory network responsible for these early events. We discuss whether this information is likely …

Editorial Overview: Environmental Physiology: Insect Environmental Physiology, Brent J. Sinclair

Biology Publications

No abstract provided.

Data Completion Methods For Improved Developmental Stage Annotation Of Drosophila Embryos In Images, Chitsanu Janyalikit

Electrical & Computer Engineering Theses & Dissertations

Drosophila melanogaster is a dominant model organism for studying the function of animal genes in initial stages of embryogenesis. Usually, images containing Drosophila gene expression patterns are captured at different developmental stages to study the interconnection of animal genes. To achieve most biologically meaningful results, gene expression images from a similar stage should be compared. Currently, biologists manually classify embryos in images into different stages, which is time intensive and infeasible for current massively produced gene expression images. Therefore, there is a need to develop an automatic system for the annotation.

Gene expression information in embryo images usually appears as …

Intranuclear Strain Measured By Iterative Warping In Cells Under Mechanical And Osmotic Stress, Jonathan T Henderson

Open Access Dissertations

The nucleus is a membrane bound organelle and regulation center for gene expression in the cell. Mechanical forces transfer to the nucleus directly and indirectly through specific cellular cytoskeletal structures and pathways. There is increasing evidence that the transferred forces to the nucleus orchestrate gene expression activity. Methods to characterize nuclear mechanics typically study isolated cells or cells embedded in 3D gel matrices. Often report only aspect ratio and volume changes, measures that oversimplify the inherent complexity of internal strain patterns. This presents technical challenges to simultaneously observe small scale nuclear mechanics and gene expression levels inside the nuclei of …

Modulation Of Host Phosphatidylinositol Phosphates By Salmonella Effector Protein Sopb, Heather L. Piscatelli

Open Access Dissertations

Salmonella spp. are gram negative bacteria capable of infecting a number of eukaryotic hosts. In humans, Salmonella infection can range anywhere from acute gastroenteritis to typhoid fever which can oftentimes be fatal.Salmonella are facultative intracellular pathogens that have acquired the ability to enter non-phagocytic cells such as those lining the intestinal epithelium. Uptake into epithelial cells is mediated by the Salmonellapathogenicity island 1 (SPI1) encoded type III secretion system (T3SS), a needle-like complex composed of over 20 proteins that translocates effector proteins directly into the host cell cytosol. Salmonella possess a second type III secretion system encoded on …