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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Characterizing The Recognition Motif And Novel Substrates Of Carm1, Sitaram Gayatri Jul 2018

Characterizing The Recognition Motif And Novel Substrates Of Carm1, Sitaram Gayatri

UT GSBS Dissertations and Theses (Open Access)

A limited pool of proteins attains vast functional repertoire due to posttranslational modifications (PTMs). Arginine methylation is a common posttranslational modification, which is catalyzed by a family of nine protein arginine methyltransferases or PRMTs. These enzymes deposit one or two methyl groups to the nitrogen atoms of arginine side-chains. Elucidating the substrate specificity of each PRMT will promote a better understanding of which signaling networks these enzymes contribute to. Although many PRMT substrates have been identified, and their methylation sites mapped, the optimal target motif for each of the nine PRMTs has not been systematically addressed. Here we describe the ...


Nanoscale Organization Of The Small Gtpase Rac1, Kelsey Maxwell May 2018

Nanoscale Organization Of The Small Gtpase Rac1, Kelsey Maxwell

UT GSBS Dissertations and Theses (Open Access)

Rac1 is a small, guanine-nucleotide binding protein that cycles between an inactive GDP-bound and active GTP-bound state to regulate actin-mediated motility, migration, and adhesion. Plasma membrane (PM) localization is essential for its biological activity. Rac1 PM targeting is directed by a C-terminal membrane anchor that encompasses a geranylgeranyl-cysteine-methyl-ester, palmitoyl, and a polybasic domain (PBD) of contiguous lysine and arginine residues. Using high-resolution imaging combined with spatial mapping analysis, I found that Rac1 forms nanoclusters on the PM. Cycling between the GTP- and GDP-bound states, Rac1 forms nanoclusters that are non-overlapping, consequently undergoing guanine nucleotide-dependent spatial segregation. I further found that ...


Investigating The Impact Of Intragenic Dna Methylation On Gene Expression, And The Clinical Implications On Tumor Cells And Associated Stroma, Michael Mcguire May 2018

Investigating The Impact Of Intragenic Dna Methylation On Gene Expression, And The Clinical Implications On Tumor Cells And Associated Stroma, Michael Mcguire

UT GSBS Dissertations and Theses (Open Access)

Investigations into the function of non-promoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated non-promoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we uncovered an enrichment of DNA methylation sites within the gene body and 3’UTR in which DNA methylation is strongly positively correlated with gene expression. We examined 32 tumor types and identified ...


The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland May 2018

The Regulation Of Dna Methylation In Mammalian Development And Cancer, Nicolas Veland

UT GSBS Dissertations and Theses (Open Access)

DNA methylation is an essential epigenetic modification in mammals, as it plays important regulatory roles in multiple biological processes, such as gene transcription, maintenance of chromosomal structure and genomic stability, genomic imprinting, retrotransposon silencing, and X-chromosome inactivation. Dysregulation of DNA methylation is associated with various human diseases. For example, cancer cells usually show global hypomethylation and regional hypermenthylation, which have been implicated in genomic instability and tumor suppressor silencing, respectively. Although great progress has been made in elucidating the biological functions of DNA methylation over the last several decades, how DNA methylation patterns and levels are regulated and dysregulated is ...


Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow Apr 2018

Discovery And Effects Of Pharmacological Inhibition Of The E3 Ligase Skp2 By Small Molecule Protein-Protein Interaction Disruptors, John K. Morrow

UT GSBS Dissertations and Theses (Open Access)

Skp2 (S-phase kinase-associated protein 2), one component of the SCF E3 ubiquitin ligase complex, directly interacts with Skp1 and indirectly associates with Cullin1 and Rbx1 to bridge the E2 conjugating enzyme with its protein substrate to execute its E3 ligase activity. Skp2 is an Fbox protein (due to it containing an Fbox domain) and it is the rate-limiting component of the SCF complex. Skp2 targets several cell-cycle regulatory proteins for ubiquitination and degradation; most notable and significant for cancer are the cyclin-dependent kinase inhibitor, p27. Skp2 is an oncogene and studies have shown that over-expression of Skp2 leads to increased ...


The Functions Of Setd5 And Mir-221 In Embryonic Stem Cell Differentiation, Tsai-Yu Chen Dec 2017

The Functions Of Setd5 And Mir-221 In Embryonic Stem Cell Differentiation, Tsai-Yu Chen

UT GSBS Dissertations and Theses (Open Access)

Embryonic stem cells (ESCs) are a widely used model system to study cellular differentiation because of their pluripotent characteristics, and ESC differentiation is an epigenetic process. In an effort to identify a new epigenetic factor that is required for ESC differentiation, the function of SETD5 in ESCs was studied for this thesis. Results show that SETD5 is essential for retinoic acid (RA)-induced differentiation of mouse ESCs and for RA-induced expression of critical developmental genes (e.g., Hoxa1 and Hoxa2) and neuron-related genes (e.g., Nestin and Pax6). SETD5 was upregulated during ESC differentiation. Additional results demonstrated that SETD5 bound ...


Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon Dec 2017

Insights Into The Therapeutic Potential Of Salt Inducible Kinase 1: A Novel Mechanism Of Metabolic Control, Randi Fitzgibbon

UT GSBS Dissertations and Theses (Open Access)

Salt inducible kinase 1 (SIK1) has been considered a stress-inducible kinase since it was first cloned in 1999. Continued efforts since this time have been dedicated to characterizing the structure and function of SIK1. Such research has laid the ground work for our understanding of SIK1 action and regulation in tissue and stimuli dependent manners. The fundamental findings of this dissertation continue in this tradition and include investigations of SIK1 regulatory mechanisms in skeletal muscle cells, the cellular and physiological effects of SIK1 loss of function in vitro and in vivo, and intracellular metabolic and mitochondrial regulation by this kinase ...


Endocytic Trafficking Of The Amyloid Precursor Protein In Rat Cortical Neurons, Sahily Reyes Dec 2017

Endocytic Trafficking Of The Amyloid Precursor Protein In Rat Cortical Neurons, Sahily Reyes

UT GSBS Dissertations and Theses (Open Access)

Amyloid-beta (Aβ) aggregation and deposition into extracellular plaques is a hallmark of the most common forms of dementia, including Alzheimer’s disease. The Aβ-containing plaques result from pathogenic cleavage of amyloid precursor protein (APP) by secretases resulting in intracellular production of Aβ peptides that are secreted and accumulate extracellularly. Despite considerable progress towards understanding APP processing and Aβ aggregation, the mechanisms underlying endosomal production of Aβ peptides and their secretion remain unclear. Using endosomes isolated from cultured primary neurons, we determined that the trafficking of APP from the endosomal membrane into internal vesicles of late endosome/multivesicular bodies (MVB) is ...


Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno Aug 2017

Preclinical Development Of Therapeutic Strategies Against Triple-Negative And Inflammatory Breast Cancer, Angie M. Torres-Adorno

UT GSBS Dissertations and Theses (Open Access)

Triple-negative (TNBC) and inflammatory (IBC) breast cancer are the most aggressive forms of breast cancer, accounting for 20% and 10% of cancer-related deaths, respectively. Among IBC cases, 30% are additionally classified with TNBC molecular pathology, a diagnosis that significantly worsens patient’s prognosis. The current lack of TNBC and IBC molecular understanding prevents the development of effective therapeutic strategies. To identify effective treatments, we explored aberrant apoptosis pathways and cell membrane fluidity as novel therapeutic targets.

We first identified an effective therapeutic strategy against TNBC and IBC by pro-apoptotic protein NOXA-mediated inhibition of the anti-apoptotic protein MCL1 following inhibition of ...


Structural And Functional Effect Of Phosphorylation On Ampa Receptors, Caitlin E. Nurik Aug 2017

Structural And Functional Effect Of Phosphorylation On Ampa Receptors, Caitlin E. Nurik

UT GSBS Dissertations and Theses (Open Access)

Structural and Functional Effect of Phosphorylation on AMPA Receptors

Cailtin Edmunds show you, BA

Advisory Professor: Vasanthi Jayaraman, Ph. D.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is the primary contributor to neuronal fast excitatory transmission, and plays a key role in learning and memory. Previous studies have established that residues S818, S831, and T840 in the C-terminal segment of GluA1 homomeric AMPA receptor are phosphorylated by PKC, and phosphorylation at these sites leads to an increase in receptor conductance. We show that the domain inclusive of those sites alters its secondary structure due to phosphorylation (using glutamate substitution as a mimic ...


Investigating The Role Of Prmt1 And Arginine Methylation Of Hsp70 In Human Pancreatic Cancer, Liang Wang Aug 2017

Investigating The Role Of Prmt1 And Arginine Methylation Of Hsp70 In Human Pancreatic Cancer, Liang Wang

UT GSBS Dissertations and Theses (Open Access)

Protein arginine methyltransferase 1 (PRMT1) is the major arginine methyltransferase, which catalyzes the addition of one or two methyl groups to the arginine residues of its substrate proteins. The best-known substrate for PRMT1 is histone, while more and more non-histone proteins are now found to be methylated by PRMT1. Dysregulation of PRMT1 is reported in several human cancer types. However, its biological roles in human pancreatic cancer initiation and development are still unclear. In the first part of this study, I found that the expression level of PRMT1 was elevated in both human and mouse pancreatic cancer tissues in immunohistochemistry ...


Gcn5 Impacts Fgf Signaling At Multiple Levels And Activates C-Myc Target Genes During Early Differentiation Of Embryoid Bodies, Li Wang Aug 2017

Gcn5 Impacts Fgf Signaling At Multiple Levels And Activates C-Myc Target Genes During Early Differentiation Of Embryoid Bodies, Li Wang

UT GSBS Dissertations and Theses (Open Access)

Precise control of gene expression during development is orchestrated by transcription factors, signaling pathways and co-regulators, with complex cross-regulatory events often occurring. Growing evidence has identified chromatin modifiers as important regulators for development as well, yet how particular chromatin modifying enzymes affect specific developmental processes remains largely unclear. Embryonic stem cells (ESCs) are self-renewing, pluripotent, and have the abilities to generate almost all cell types in adult tissues. The dual capacity of ESCs to self-renew and differentiate offers unlimited potential for studying gene regulation events at specific developmental stages in vitro that parallel developmental events during embryogenesis in vivo.

In ...


Fret-Based Investigations Of The Structure-Function Relationships In The Nmda Receptor, Drew M. Dolino May 2017

Fret-Based Investigations Of The Structure-Function Relationships In The Nmda Receptor, Drew M. Dolino

UT GSBS Dissertations and Theses (Open Access)

The N-methyl-D-aspartate (NMDA) receptor is one member of a class of proteins known as the ionotropic glutamate receptors. Ionotropic glutamate receptors mediate the majority of excitatory neurotransmission in the central nervous system, with the NMDA receptor standing out among these receptors for its requirement of a co-agonist, its magnesium-block-based coincidence detection, its slow kinetics, its calcium permeability, its allosteric modulation, and its especially important functional roles in synaptic plasticity, excitotoxicity, and more. In recent years, a wealth of structural information has come about describing endpoint structures to high resolution, but such structures are unable to fully resolve the movements ...


Analysis Of The Biochemical And Cellular Activities Of Substrate Binding By The Molecular Chaperone Hsp110/Sse1, Veronica M. Garcia May 2017

Analysis Of The Biochemical And Cellular Activities Of Substrate Binding By The Molecular Chaperone Hsp110/Sse1, Veronica M. Garcia

UT GSBS Dissertations and Theses (Open Access)

Molecular chaperones ensure protein quality during protein synthesis, delivery, damage repair, and degradation. The ubiquitous and highly conserved molecular chaperone 70-kDa heat-shock proteins (Hsp70s) are essential in maintaining protein homeostasis by cycling through high and low affinity binding of unfolded protein clients to facilitate folding. The Hsp110 class of chaperones are divergent relatives of Hsp70 that are extremely effective in preventing protein aggregation but lack the hallmark folding activity seen in Hsp70s. Hsp110s serve as Hsp70 nucleotide exchange factors (NEF) that facilitate the Hsp70 folding cycle by inducing release of protein substrate from Hsp70, thus recycling the chaperone for a ...


Role And Regulation Of Sphingosine 1-Phosphate In Erythrocyte, Kaiqi Sun May 2017

Role And Regulation Of Sphingosine 1-Phosphate In Erythrocyte, Kaiqi Sun

UT GSBS Dissertations and Theses (Open Access)

Sphingosine 1-phosphate (S1P) is a bioactive signaling sphingolipid produced in every mammalian cell. It plays a variety of important roles both in and outside of cells. S1P is highly enriched in mature erythrocytes because of the high enzymatic activity of the S1P-generating enzyme Sphingosine Kinase 1 (Sphk1) and the absence of S1P degrading enzymes. Erythrocytes are considered only a major reservoir for S1P because they supply S1P to the circulation for the regulation of various physiological processes which include but are not limited to immune cell trafficking, endothelial integrity and hematopoietic stem cell mobilization. However, if S1P plays a role ...


The Role Of Adenosine Signaling In Mature Erythrocytes And Erythroid Progenitors, Hong Liu May 2017

The Role Of Adenosine Signaling In Mature Erythrocytes And Erythroid Progenitors, Hong Liu

UT GSBS Dissertations and Theses (Open Access)

Adenosine is a ubiquitous nucleoside in almost all the cells throughout our bodies. It is highly induced particularly under hypoxia or energy depletion conditions. Adenosine functions as a critical ligand, after binding to membrane-associated adenosine receptors, adenosine initiates a downstream signaling cascade and subsequently contributes to functions of nervous system, immune response, vascular function and even metabolism.

Hypoxia is a condition with limited O2 availability in the whole body or a region of the body. It is a major consequence of many respiratory and cardiovascular diseases, as well as for people living and working at high altitudes or other ...


Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang Dec 2016

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

UT GSBS Dissertations and Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes ...


Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez Aug 2016

Investigating The Roles Of Δnp63 As A Suppressor Of Migration, Invasion, And Metastasis, Ramon E. Flores Gonzalez

UT GSBS Dissertations and Theses (Open Access)

Cancer is one of the leading causes of death and disease in the world. Considerable resources are spent to study and understand cancer, with the hope of developing new treatments and eventually cures that will help millions of people. Efforts to understand cancer are hindered by its inherent complexity and instability. Nonetheless, understanding the basics of tumor development and progression are the key to focused on studying the role of ΔNp63 in cancer, a p53 family member known to be involved in epithelial development, microRNA biogenesis, and stem cell maintenance. Using the strength of in vivo mouse models, we found ...


Circumventing Cisplatin Resistance In Ovarian Cancers Through Reactivation Of P53 By Non-Cross-Resistant Platinum Analogs, Michelle Martinez-Rivera Aug 2016

Circumventing Cisplatin Resistance In Ovarian Cancers Through Reactivation Of P53 By Non-Cross-Resistant Platinum Analogs, Michelle Martinez-Rivera

UT GSBS Dissertations and Theses (Open Access)

Abstract

CIRCUMVENTING CISPLATIN RESISTANCE IN OVARIAN CANCERS THROUGH REACTIVATION OF P53 BY NON-CROSS-RESISTANT PLATINUM ANALOGS

Michelle Martinez-Rivera, B.S.

Advisory Professor: Zahid H. Siddik, Ph.D.

Cisplatin (cis-Pt), an anticancer platinum (Pt) drug, is used widely in the treatment of several malignancies, such as ovarian cancer. This Pt compound induces DNA damage, which results in p53 activation through post-translational modifications, mainly phosphorylation, culminating in execution of programmed cell-death. However, despite initial therapeutic response to cis-Pt, clinical resistance to this drug emerges leading to disease progression. Pt-resistance phenotypes have been associated with dysfunction in the p53 signaling pathway. Therefore, an effort ...


¬¬Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li Aug 2016

¬¬Define The Epigenetic Profiles And Subtype-Specific Genes Of Breast Cancer, Wenqian Li

UT GSBS Dissertations and Theses (Open Access)

Molecular profiling has identified 5 distinct subtypes of breast cancer, luminal A, luminal B, HER2-enriched, basal-like, and claudin-low breast cancer. These 5 subtypes correlate with hormone response, patient prognosis, and response to therapy. Although steady state gene expression patterns have been explored using expression microarrays, very little is known about the initial, disease-driving transcriptional changes in these cancers or epigenetic changes associated with the differential gene expression signatures. Defining these changes may provide new insights into the mechanisms by which these subtypes arise, as well as new avenues for breast cancer prevention, diagnosis, and treatment. Using Chromatin Immunoprecipitation sequencing and ...


The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan May 2016

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

UT GSBS Dissertations and Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced ...


Developing And Using Methyl-Specific Antibodies To Study The Biological Roles Of Arginine Methylation, Vidyasiri Vemulapalli May 2016

Developing And Using Methyl-Specific Antibodies To Study The Biological Roles Of Arginine Methylation, Vidyasiri Vemulapalli

UT GSBS Dissertations and Theses (Open Access)

Arginine residues can be modified in three different ways to produce asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and monomethylarginine (MMA). These modifications are catalyzed by a family of nine protein arginine methyltransferases (PRMT1-9), which are of three types (I, II, and III). The majority of Type I enzymes asymmetrically dimethylate Glycine- and Arginine-rich (GAR) motifs, except for PRMT4, which methylates Proline-, Glycine-, and Methionine-rich (PGM) motifs. The same substrates (GAR or PGM motifs) can also be dimethylated by PRMT5 in a symmetric fashion. However, it is not clear whether there are dedicated residues within these motifs for ADMA and SDMA ...


Cll Metabolism Is Regulated By Prognostic Factors, Modulated By Stroma And Abrogated By Pi3k Inhibition, Hima Vangapandu May 2016

Cll Metabolism Is Regulated By Prognostic Factors, Modulated By Stroma And Abrogated By Pi3k Inhibition, Hima Vangapandu

UT GSBS Dissertations and Theses (Open Access)

Metabolism of chronic lymphocytic leukemia (CLL), a disease characterized by the relentless accumulation of mature B cells has been little explored. Bone marrow stromal cells provide a survival benefit to CLL cells, in part through PI3K/AKT pathway. Compared with proliferative B-cell lines, metabolic fluxes of oxygen and lactate were low in quiescent malignant B lymphocytes from CLL patients. Glycolysis (extracellular acidification rate, ECAR) was consistently low in CLL samples, but oxygen consumption (OCR) varied considerably. Higher OCR was associated with poor prognostic factors such as ZAP 70 positivity, unmutated IgVH, high β2M levels, and higher Rai stage. Co-culture with ...


Preeclampsia: The Roles Of Acute Inflammation And Intrauterine Stress, Nicholas Parchim May 2016

Preeclampsia: The Roles Of Acute Inflammation And Intrauterine Stress, Nicholas Parchim

UT GSBS Dissertations and Theses (Open Access)

Preeclampsia (PE) is a severe, acute disease of pregnancy affecting approximately 8% of pregnant women after week 20 of gestation. PE is characterized by hypertension and renal damage reflected by proteinuria and has significant morbidity to both mother and fetus. Maternal symptoms range from headaches, nausea, edema, to visual changes, but once maternal symptoms present, damage to the fetus has begun. Mothers who progress untreated through the disease can also experience a condition called eclampsia characterized by seizure, coma, and, ultimately, death. PE-affected newborns experience features similar to prematurity—abnormal lung and renal development, intrauterine growth retardation (IUGR), and, possibly ...


The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy Dec 2015

The Tumor Suppressor Notch Inhibits Head And Neck Squamous Cell Carcinoma (Hnscc) Tumor Growth And Progression By Modulating Proto-Oncogenes Axl And Ctnnal1 (Α-Catulin), Shhyam Moorthy, Shhyam Moorthy

UT GSBS Dissertations and Theses (Open Access)

Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common malignancy worldwide, with roughly 300,000 cancer related deaths occurring globally each year. The survival of patients with HNSCC has not changed significantly over the past decade, leading investigators to search for promising molecular targets. To identify new treatment targets and biomarkers that could better guide therapy, we previously characterized the genomic alterations from primary HNSCC patient samples. We were among the first to discover that NOTCH1 is one of the most frequently mutated genes in this cancer type. The spectrum of inactivating NOTCH1 mutations in HNSCC ...


Molecular Regulation Of Vascular Calcification In Murine Models Of Atherosclerosis, Shanshan Gao Dec 2015

Molecular Regulation Of Vascular Calcification In Murine Models Of Atherosclerosis, Shanshan Gao

UT GSBS Dissertations and Theses (Open Access)

Background: Calcification occurs often in the atherosclerotic lesions of patients with coronary heart disease and animals with hypercholesterolemia, such as apolipoprotein-E deficient (ApoE-/-) mice. However, the mechanism(s) underlying the development of calcification in atherosclerosis remains unclear. ApoE acts as a lipid transporter, but also has been recognized as a potential regulator of osteogenesis. Little information is available as to whether ApoE has any direct impact on osteogenesis and calcification in vascular smooth muscle cells (VSMC). Several signal transduction pathways play a role in regulation of calcification, including the Wnt/β-catenin system and potentially GTAP, an ubiquitin-conjugating enzyme responsible for ...


Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd Dec 2015

Normal Glycolytic Enzyme Activity Is Critical For Hypoxia Inducible Factor-1a Activity And Provides Novel Targets For Inhibiting Tumor Growth, Geoffrey Grandjean Phd

UT GSBS Dissertations and Theses (Open Access)

Normal Glycolytic Enzyme Activity is Critical for Hypoxia Inducible Factor-1α Activity and Provides Novel Targets for Inhibiting Tumor Growth

By Geoffrey Grandjean

Advisory Professor: Garth Powis, D. Phil

Unique to proliferating cancer cells is the observation that their increased need for energy is provided by a high rate of glycolysis followed by lactic acid fermentation in a process known as the Warburg Effect, a process many times less efficient than oxidative phosphorylation employed by normal cells to satisfy a similar energy demand [1]. This high rate of glycolysis occurs regardless of the concentration of oxygen in the cell and is ...


Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith Aug 2015

Prophylactic Cranial Irradiation Reduces The Incidence Of Brain Metastasis In A Mouse Model Of Metastatic Breast Cancer, Daniel L. Smith

UT GSBS Dissertations and Theses (Open Access)

Prophylactic cranial irradiation (PCI) is a preventative whole-brain irradiation technique used to reduce the incidence of brain metastasis and improve overall survival in select patients with small cell lung cancer and acute lymphoblastic leukemia. A population of breast cancer patients – stage IV, HER2+ or triple-negative – has emerged as having a high risk of developing brain metastases. Because only 10-20% of breast cancer patients diagnosed with brain metastases survive longer than one year, in this high-risk population the benefit of PCI – potential for reduced incidence of brain metastasis and improved overall survival – may outweigh the risks – radiation toxicity. The objective of ...


Gating Mechanisms Of The Canonical Trp Channel Isoform Trpc4, Dhananjay P. Thakur Aug 2015

Gating Mechanisms Of The Canonical Trp Channel Isoform Trpc4, Dhananjay P. Thakur

UT GSBS Dissertations and Theses (Open Access)

Non-selective cation channels formed by Transient Receptor Potential Canonical (TRPC) proteins play important roles in regulatory and pathophysiological processes. These channels are known to be activated downstream from phospholipase C (PLC) signaling. However, the mechanism by which the PLC pathway activates TRPC4/C5 remains unclear. Uniquely, TRPC4 is maximally activated only when two separate G protein pathways, Gq/11 and Gi/o, are co-stimulated, making it a coincidence detector of Gq/11- and Gi/o -coupled receptor activation. Using HEK293 cells co-expressing mouse TRPC4β and selected G protein-coupled receptors, I observed that coincident stimulation of G ...


Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen Aug 2015

Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen

UT GSBS Dissertations and Theses (Open Access)

The past decade has witnessed an era of RNA biology; despite the considerable discoveries nowadays, challenges still remain when one aims to screen RNA-interacting small molecule or RNA-interacting protein. These challenges imply an immediate need for cost-efficient while predictive computational tools capable of generating insightful hypotheses to discover novel RNA-interacting small molecule or RNA-interacting protein. Thus, we implemented novel computational models in this dissertation to predict RNA-ligand interactions (Chapter 1) and RNA-protein interactions (Chapter 2).

Targeting RNA has not garnered comparable interest as protein, and is restricted by lack of computational tools for structure-based drug design. To test the potential ...