Understanding The Regulatory Context And Mechanism Of Hlh-25 Mediated Transcriptional Repression,
2023
James Madison University
Understanding The Regulatory Context And Mechanism Of Hlh-25 Mediated Transcriptional Repression, Dagmawi Mamo
Masters Theses, 2020-current
The HES family of transcription factors are primarily repressors of transcription that play critical roles in mammalian embryogenesis by regulating cell differentiation and proliferation. Proper functioning of HES proteins is crucial in humans, as mutations or misexpression of HES1 is associated with lung, pancreas, colon, and other cancers. HES1 may mediate short-range or long-range repression through DNA-binding and or protein-protein interactions with other factors. However, prior genetic studies have not fully elucidated how the context-specific binding of HES1, or its C. elegans ortholog HLH-25, promotes the repression of transcription. Characterization of the cis-regulatory context and mechanism of HLH-25 mediated repression …
Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors,
2023
University of Nebraska Medical Center
Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen
Theses & Dissertations
Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …
Targeting The Cxcr1/2 Axis In Pancreatic Ductal Adenocarcinoma,
2023
University of Nebraska Medical Center
Targeting The Cxcr1/2 Axis In Pancreatic Ductal Adenocarcinoma, Caitlin Molczyk
Theses & Dissertations
Pancreatic ductal adenocarcinoma (PDAC) is notoriously challenging to diagnose and treat. This tumor has an aggressive phenotype and benign clinical features until severe disease dissemination, which makes it too late to eradicate. Although it is only the 10th most common cancer in the United States, it is the fourth leading cause of cancer-related deaths. The treatment options are complicated further due to tumor heterogeneity, meaning not all tumor cells are in the same state phenotypically or epigenetically. They also express cytokines, chemokines, and receptors differently. Here we explore the usage of CXCR1 and CXCR2 and their ligands in PDAC tumor …
Parkin Ubiquitination Of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression,
2023
Thomas Jefferson University
Parkin Ubiquitination Of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression, Minjeong Yeon, Irene Bertolini, Ekta Agarwal, Jagadish C Ghosh, Hsin-Yao Tang, David W. Speicher, Frederick Keeney, Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F. Plow, Lucia R. Languino, Emmanuel Skordalakes, M Cecilia Caino, Dario C. Altieri
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does …
Investigating The Phenotypic Effects Of Ring1- And Yy1-Binding Protein (Rybp) In Glioblastoma Multiforme,
2023
Winthrop University
Investigating The Phenotypic Effects Of Ring1- And Yy1-Binding Protein (Rybp) In Glioblastoma Multiforme, Ronald W. Bucher
Graduate Theses
Glioblastoma multiforme (GBM) is an aggressive form of brain cancer that has horrendous survival outcomes with the use of current therapies. Further study into its molecular mechanisms will inform development of new, more effective treatments. The Polycomb protein RING1- and YY1- Binding Protein (RYBP) has emerged as an important gene in multiple cancers. In complex with other Polycomb proteins, RYBP acts to repress regions of chromatin, though it also performs other functions independent of these complexes. RYBP has a tumor suppressive role in various cancers, but may act as an oncogene in others, demonstrating its context-specific effects. The role of …
Studying The Phosphorylation Of Isocitrate Dehydrogenase In Humans,
2023
University of Arkansas, Fayetteville
Studying The Phosphorylation Of Isocitrate Dehydrogenase In Humans, Hannah Smith
Chemistry & Biochemistry Undergraduate Honors Theses
Isocitrate dehydrogenase is an important enzyme in the citric acid cycle where it catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate. While there are three isoforms of isocitrate dehydrogenase (IDH1, IDH2, and IDH3), this research will focus on IDH1. The phosphorylation of isocitrate dehydrogenase is a process that has been linked to the formation of both luminal-like and basal-like breast cancer. Despite these correlations, the mechanisms that cause breast cancer development are unknown. To examine this, an enzyme activity assay for each phosphorylation variant and crystallization were conducted. The results of these indicate that phosphorylation at each site (IDH1-T77, IDH1-S188, …
Investigation Of The Role Of Dax-1 In The Hpa Axis In Human Adrenal Cells,
2023
University of San Francisco
Investigation Of The Role Of Dax-1 In The Hpa Axis In Human Adrenal Cells, Katerina N. Fargas
Undergraduate Honors Theses
DAX-1 is a nuclear hormone orphan receptor that plays a key role in the development of reproductive tissues and steroid hormone production. The hypothalamic-pituitary-adrenal axis is the pathway for steroid hormone production, primarily glucocorticoids, mineralocorticoids, and adrenal androgens, in the human body. The mechanisms of DAX-1 in hormone production in the adrenal cortex of the HPA axis are not completely understood and, therefore, were the focus of this honors thesis research project. Due to the high level of DAX-1 expression, SW13 adrenal carcinoma cells were conducted for these experiments. We investigated whether glucocorticoids, specifically the synthetic glucocorticoid dexamethasone, had any …
A Dna-Peptide Crosslink (Dpc) Increases Mutagenicity In Sos-Induced Escherichia Coli,
2023
University of Connecticut
A Dna-Peptide Crosslink (Dpc) Increases Mutagenicity In Sos-Induced Escherichia Coli, Alessandra Bassani
Honors Scholar Theses
Bacteria, such as Escherichia coli, have an inducible system in response to DNA damage termed the SOS response. This system is activated when the replicative DNA polymerase (Pol) III encounters a lesion, uncouples from DNA helicase, and single-stranded DNA (ssDNA) accumulates at the replication fork. In this study, we investigated DNA-peptide crosslink (DpC), a common lesion that results from cross-linking of proteins or peptides, UV irradiation, and alkylating agents. To increase survival following formation of a lesion, the SOS response can utilize homologous recombination, translesion synthesis (TLS), or excision repair. With TLS, the levels of DNA Pol II, IV, …
Computational Modeling Of The Fanconi Anemia Gene Network And Its Connection To Cancer,
2023
University of Arkansas, Fayetteville
Computational Modeling Of The Fanconi Anemia Gene Network And Its Connection To Cancer, Alyssa Warren-Belford
Biological Sciences Undergraduate Honors Theses
Fanconi anemia (FA) is a rare genetic condition in which the cell’s DNA repair machinery is dysregulated, significantly increasing the chances of tumorigenesis. Further research is being done in order to improve patient outcomes and incidences of cancer. Our group created a computational model of the FA DNA repair gene network, which removes interstrand crosslinks found in damaged DNA and repairs it so DNA synthesis can continue. Computer simulations show the number of DNA damage indicators decreased as the pathway continued. This was expected as the FA pathway repairs DNA damage. The goal of this project was to provide further …
Elucidating Mechanisms Involved In Host Microbial-Tumor Interactions,
2023
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Elucidating Mechanisms Involved In Host Microbial-Tumor Interactions, Vidhi Chandra
Dissertations and Theses (Open Access)
Cancer is a rising cause of mortality worldwide. Microbiota is the collection of micro-organisms that live inside our bodies and can impact the host health and disease by interacting with the immune and metabolic systems. The relationship between the microbiota and cancer is complex. Gut and intratumoral microbiota can affect cancer development and progression by influencing patient outcomes and therapy responsiveness in several cancer types. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment (TME) which limits efficacy of most available therapies. The tumoral niche provides a privileged microenvironment for microbial colonization that can …
Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants,
2023
The Texas Medical Center Library
Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad
Dissertations and Theses (Open Access)
Missense mutations in the DNA binding domain of the Trp53 gene are characterized as structural (p53R172H) or contact (p53R245W) mutations based on their effect on the conformation of the protein. These mutations show gain-of-function activities such as increased metastatic incidence as compared to p53 loss, often mediated by their interaction with a repertoire of transcription factors. These interactions are largely context specific. In order to understand the mechanisms by which these mutations drive osteosarcoma progression, we created a mouse model, wherein either the p53 structural mutant p53R172H, or the contact mutant, p53R245W, are expressed specifically in …
Oncolytic Virus Immunotherapy: Development And Potential For Cancer Treatment,
2023
University of Connecticut
Oncolytic Virus Immunotherapy: Development And Potential For Cancer Treatment, Olivia Guinness
Honors Scholar Theses
The American Cancer Society estimates that in 2023, 1,958,310 new cancer cases and 609,820 cancer deaths will occur in the United States [16]. A promising therapeutic option that has been supported by recent clinical trials is the use of oncolytic viruses to treat malignant tumors. The mechanism of action of existing treatments, such as chemotherapy, radiotherapy, and surgery, differs from that of oncolytic virus therapy because oncolytic viruses are able to affect cancer cells with specificity, minimizing side effects. When infecting a normal, non-cancerous cell, oncolytic viruses do not replicate, leaving healthy cells unaffected. In tumor cells, oncolytic viruses will …
Functional Analysis Of Daxx In Tumorigenesis Of Pancreatic Neuroendocrine Tumors And Embryonic Development,
2023
The Texas Medical Center Library
Functional Analysis Of Daxx In Tumorigenesis Of Pancreatic Neuroendocrine Tumors And Embryonic Development, Chang Sun
Dissertations and Theses (Open Access)
Death domain-associated protein 6 (Daxx) is a histone chaperone specific to Histone 3.3 (H3.3). DAXX interacts with ATRX forming a chromatin remodeling complex, which deposits H3.3 into telomeric and pericentric region of the genome. The importance of Daxx was manifested in embryonic development. The loss of Daxx leads to early lethality in mouse embryos around E6.5. Moreover, sequencing studies have revealed the importance of DAXX in human tumors. Mutually exclusive mutations in DAXX and ATRX occur in about 30% of pancreatic neuroendocrine tumors (PanNETs). Although lots of progress has been made in studying functions of DAXX, we still do not …
P53 Dimers Elicit Unique Tumor Suppressive Activities Through An Altered Metabolic Program,
2023
The Texas Medical Center Library
P53 Dimers Elicit Unique Tumor Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto
Dissertations and Theses (Open Access)
p53 is the most frequently mutated tumor suppressor in human cancer. As a tetrameric transcription factor, mutation of the p53 Tetramerization Domain (TD) is a mechanism by which cancers abrogate wild-type (WT) p53 function. p53 TD mutations result in a protein that preferentially forms monomers or dimers. These are also normal p53 states under basal cellular conditions. Although it is accepted that tetrameric p53 is required for full tumor suppressive activities, the physiological relevance of monomeric and dimeric states of p53 is not well understood. We have established in vivo models for monomeric and dimeric p53 which model Li-Fraumeni Syndrome …
Uncovering Molecular Targets To Overcome Immunosuppression In Non-Small Cell Lung Cancer With Acquired Tki Resistance,
2023
The Texas Medical Center Library
Uncovering Molecular Targets To Overcome Immunosuppression In Non-Small Cell Lung Cancer With Acquired Tki Resistance, Sonia A. Patel
Dissertations and Theses (Open Access)
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Targeted therapeutic agents, such as epidermal-like growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting vascular endothelial growth factor (VEGF/R), can effectively inhibit upregulated signaling pathways driving tumorigenesis in NSCLC and many other cancers. Unfortunately, however, resistance to such targeted therapies inevitably arise in most patients and can occur through a variety of resistance mechanisms including genomic alterations and upregulation of bypass pathways. Additionally, patients who have acquired resistance to these targeted agents typically have tumors characterized by an immunosuppressive tumor microenvironment and thus …
Kir-Based Inhibitory Cars Overcome Car-Nk Cell Trogocytosis-Mediated Fratricide And Tumor Escape,
2023
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Kir-Based Inhibitory Cars Overcome Car-Nk Cell Trogocytosis-Mediated Fratricide And Tumor Escape, Ye Nmn Li
Dissertations and Theses (Open Access)
Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted the transfer of the CAR-cognate-antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their targets, (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both …
Y Chromosome Gene Kdm5d Epigenetically Drives Sex Differences In Colorectal Cancer,
2023
The Texas Medical Center Library
Y Chromosome Gene Kdm5d Epigenetically Drives Sex Differences In Colorectal Cancer, Jiexi Li
Dissertations and Theses (Open Access)
Sex exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase …
Regulation Of De Novo And Maintenance Dna Methylation By Dnmt3a And Dnmt3b,
2023
The Texas Medical Center Library
Regulation Of De Novo And Maintenance Dna Methylation By Dnmt3a And Dnmt3b, Yang Zeng
Dissertations and Theses (Open Access)
DNA methylation (5-methylcytosine, 5mC) is essential for the regulation of gene expression and integrity of the mammalian genome. It occurs predominantly in the context of CpG dinucleotides to form a symmetrical pattern on both DNA strands, which allows DNA methylation patterns to be semi-conservatively maintained during DNA replication. There are two classes of DNA methyltransferases (DNMTs): DNMT3A and DNMT3B function primarily as de novo methyltransferases that establish DNA methylation patterns, whereas DNMT1 is the major enzyme responsible for maintaining DNA methylation patterns by converting hemi-methylated CpGs to fully methylated CpGs during DNA replication. Two accessory factors also play critical regulatory …
Hypoxia Activated Prodrug And Anti-Angiogenic Therapy Cooperate To Treat Pancreatic Cancer But Elicit Immune Suppressive G-Mdsc Infiltration,
2023
The Texas Medical Center Library
Hypoxia Activated Prodrug And Anti-Angiogenic Therapy Cooperate To Treat Pancreatic Cancer But Elicit Immune Suppressive G-Mdsc Infiltration, Arthur Liu
Dissertations and Theses (Open Access)
We previously showed that the hypoxia-activated prodrug TH-302 (Evofosfamide) reduces intratumoral hypoxia through a tissue remodeling process, initiates tumor vasculature reorganization, and sensitizes aggressive, spontaneous murine models of prostate cancer to immune checkpoint blockade (ICB). In a clinical trial testing the combination of TH-302 with cytotoxic T-lymphocyte-associated protein (CTLA-4) blockade (NCT03098160) a subset of metastatic, ICB refractory patients showed prolonged progression free survival. While these studies highlight hypoxia as therapeutically tractable, we lack a complete understanding of the contribution of the tumor vasculature to hypoxia reduction therapy, as well as the downstream consequences of hypoxia reduction on the cellular composition …
Regulation And Function Of Zeb1 Acetylation In Lung Adenocarcinoma Progression And Metastasis,
2023
The Texas Medical Center Library
Regulation And Function Of Zeb1 Acetylation In Lung Adenocarcinoma Progression And Metastasis, Mabel Perez-Oquendo
Dissertations and Theses (Open Access)
Lung cancer metastasis is leading the causes of cancer-related mortality in the United States and worldwide. Epithelial-to-mesenchymal transition (EMT) is a model for metastasis that results in loss of specialized epithelial cell contacts and acquisition of mesenchymal invasive capacity. Zinc finger E-box-binding homeobox 1 (ZEB1) recognizes and binds to E-boxes of epithelial gene promoters to repress its transcription. ZEB1 has inconsistent molecular weights, which have been attributed to post-translational modifications (PTMs). In the presented dissertation, I specifically addressed the gap in the molecular mechanisms by which PTMs of ZEB1 regulate its ability to induce EMT and how its activity might …
