Biochemistry Commons^™

Development And Biological Evaluation Of Selective Small-Molecule Inhibitors Of The Human Cytochrome P450 1b1, Austin Hachey

Theses and Dissertations--Chemistry

The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this …

Characterization Of The Influence Of A Small Molecule Inhibitor On Ras-Related Proteins Interactions, Emilio Duverna

Graduate Theses and Dissertations

The Ras superfamily of small G proteins are involved in cell-signaling processes that, if not regulated, may lead to cell multiplication, apoptosis inhibition, and tumorigenesis. They function as molecular switches, which through GTP/GDP exchange cycle, switch on or off cellular activities. Overexpression and/or hyperactivity of these proteins have been linked to many diseases including various cancers. CDC42, a member of the Rho subfamily of the Ras superfamily of small G proteins, participates in the regulation of many cellular processes including cell adhesion, mitosis, and cytoskeletal rearrangements. CDC42 binds to and activates many effector proteins including CDC42-activated kinase (ACK). Abnormal activities …

Inhibition Of De Novo And The Prion-Like Spread Of Amyloidogenesis Using In Vitro And In Vivo Disease Models, Johnson Anazoba Joseph

Electronic Theses and Dissertations

The aberrant fibrous, extracellular, and intracellular proteinaceous deposits in cells, organs and tissues are referred to as amyloids. These deposits are dominated by β-sheet structures that have been implicated in several neurodegenerative diseases and cancer. In this work, the types of amyloidosis studied include Parkinson’s disease (PD) using UA196 and NL5901 strains of Caenorhabditis elegans (C. elegans), Alzheimer’s disease (AD) using GMC101 strain of C. elegans, and cancer-associated mutant p53 aggregation in MIA PaCa-2 mutant cells. Several molecules including SK-129, NS132, NS163, bexarotene, a polyphenol (-)-epi-gallocatechine gallate (EGCG), ADH40, RD148, and RD242 were screened in vitro and in …

Functional Characterization Of Cancer-Associated Dna Polymerase Ε Variants, Stephanie R. Barbari

Theses & Dissertations

Replicative DNA polymerases ε (Polε) and δ (Polδ) achieve high fidelity DNA synthesis through a precise balance of polymerization and exonucleolytic proofreading. Errors that escape proofreading are corrected by DNA mismatch repair (MMR). Ultramutated human cancers with proficient MMR carry alterations in the exonuclease domain of Polε, which were initially predicted to abolish proofreading. However, functional studies in yeast of the most recurrent Polε-P286R variant suggested defects beyond a loss of exonuclease activity. Indeed, biochemical analysis of the yeast Polε-P286R analog revealed increased polymerization capacity in addition to decreased proofreading, which enables efficient mismatch extension and bypass of replication-blocking non-B …

Glucose Metabolism Of Breast Cancer Sub-Clones That Preferentially Metastasize To The Lungs And Bone, Anna G. Skubiz

Honors Theses

Malignant breast cancers exhibit preferential metastasis to bone and lung (1). While changes in gene expression in lung-specific (LM) and bone-specific metastasis (BoM) lines derived from the MDA-MB-231 breast cancer line have been identified, few metabolic genes are differentially expressed; thus it is unknown if tissue-specific metabolic reprogramming occurs. Two hallmarks of cancer cells are an altered metabolic phenotype characterized by enhanced conversion of glucose to lactate in spite of adequate oxygen availability for complete mitochondrial oxidation of this substrate (referred to as aerobic glycolysis or the Warburg effect) and a greater dependence on glutamine. These changes in primary tumor …

An Oxanthroquinone Derivative Disrupts Ras Plasma Membrane Localization And Function By Inhibition Of Acylpeptide Hydrolase And Perturbation Of Sphingomyelin Metabolism, Lingxiao Tan

Dissertations & Theses (Open Access)

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examined the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalized HRAS and KRAS from the PM with similar potency and disrupted the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization …

Effectiveness And Mechanism Of Action Of Modified Porphyrins For Photodynamic Therapy Of Triple Negative Breast Cancer Cells, Hannah Brandon

Honors Theses

Triple negative breast cancer (TNBC) is a particularly aggressive form of breast cancer that lacks the three molecules typically targeted for treatment. Standard treatment methods leave much to be desired--the rates of metastasis and recurrence are high and the prognosis for most patients with TNBC is poor. One potential treatment for TNBC is photodynamic therapy (PDT), which uses compounds called photosensitizers that are taken up by all tissues in the body. The tumor is exposed to light, activating the photosensitizer and creating reactive oxygen species that cause cell death. This method is relatively pain-free, effective, and does not harm cells …

Effectiveness And Mechanism Of Action Of Modified Porphyrins For Photodynamic Therapy Of Triple Negative Breast Cancer Cells, Alex Abbott

Honors Theses

Triple negative breast cancer is an aggressive family of cancers that are extremely difficult to treat. Therefore, the prognosis for most patients with TNBC is poor. The goal of this research is to determine if photodynamic therapy could be a possible option for TNBC in the future using MDA-MB231 cells. MDA-MB231 cells were originally isolated from a patient with triple negative breast cancer and have been used for many studies, so they would work well for this study. Photodynamic therapy uses compounds called photosensitizing agents which are taken up by all tissues in the body and then activated by light. …

The E. Coli Protein Ybgl: A Novel Dna Repair Enzyme?, Mason H. Conen, Brooke D. Martin, Kent Sugden, Savannah Whitfield

Undergraduate Theses, Professional Papers, and Capstone Artifacts

Cr(V) is a carcinogen that oxidizes guanine aggressively to form spiroiminodihydantion (Sp) and guanidinohydantoin (Gh), both of which contain an unusual hydantoin moiety that cause G→T transversion mutations at a high rate. Endonuclease VIII (nei) can recognize and excise these oxidation products from DNA and is translated as one of five protein products of the Nei operon in Escherichia coli (E. coli). However, the functions of the other four proteins remain unknown. To address this gap in knowledge, we focused on one of the four that immediately precedes nei, the ybgL protein. Previous work by our group has suggested a …

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

Dissertations & 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 …

Characterization Of Numb As A Regulator Of Anaplastic Lymphoma Kinase, Ran Wei

Electronic Thesis and Dissertation Repository

Cellular events rely on protein-protein interactions that are often mediated by modular domains which recognize particular sequence motifs in binding partners. The NUMB protein is the first described cell fate determinant and multifaceted adaptor that is involved in a wide variety of cellular events. NUMB mainly mediates protein interactions via its modular PTB domain. Here we present a systematic investigation of the NUMB-PTB interactome by employing an integrative strategy combining both protein and peptide arrays. We profiled NUMB-PTB binding specificity and interacting proteins genome-wide. The receptor tyrosine kinases (RTKs) are found highly enriched in the interactome, raising the possibility that …

Interaction Between Atm Kinase And P53 In Determining Glioma Radiosensitivity, Syed F. Ahmad

Theses and Dissertations

Glioblastoma multiforme (GBM) is the most common primary brain tumor. Studies have shown that targeting the DNA damage response can sensitize cancer cells to DNA damaging agents. Ataxia telangiectasia mutated (ATM) is involved in signaling DNA double strand breaks. Our group has previously shown that ATM inhibitors (ATMi) sensitize GBM cells and tumors to ionizing radiation. This effect is greater when the tumor suppressor p53 is mutated.

The goals of this work include validation of a new ATM inhibitor, AZ32, and elucidation of how ATMi and p53 status interact to promote cell death after radiation. We propose that ATMi and …

Nitric Oxide Synthase Activity And Its Modulation In The Treatment Of Colorectal Cancer, Asim Alam

Theses and Dissertations

The American Cancer Society estimates more than 141,000 new cases of and about 50,000 deaths from colorectal cancer every year. Treatment options include surgery, radiation therapy and targeted therapies such as anti-angiogenics. However, no therapies address the key driving factor of colorectal cancer: inflammation. It is well known that chronic inflammatory conditions such as Crohn’s Disease, ulcerative colitis, diabetes, obesity and cigarette smoking all elevate the risk of developing colorectal cancer. One of the hallmarks of chronic inflammation is the elevated levels of reactive oxygen/nitrogen species (ROS/RNS). A primary source of these ROS/RNS is uncoupled Nitric Oxide Synthase (NOS). Under …

A Study On The Function Of 14-3-3sigma In Regulating Cancer Energy Metabolism, Liem M. Phan, Liem M. Phan

Dissertations & Theses (Open Access)

Metabolic reprogramming has been shown to be a major cancer hallmark providing tumor cells with significant advantages for survival, proliferation, growth, metastasis and resistance against anti-cancer therapies. Glycolysis, glutaminolysis and mitochondrial biogenesis are among the most essential cancer metabolic alterations because these pathways provide cancer cells with not only energy but also crucial metabolites to support large-scale biosynthesis, rapid proliferation and tumorigenesis. In this study, we find that 14-3-3σ suppresses all these three metabolic processes by promoting the degradation of their main driver, c-Myc. In fact, 14-3-3s significantly enhances c-Myc poly-ubiquitination and subsequent degradation, reduces c-Myc transcriptional activity, and down-regulates …

Characterization Of A Tumour Suppressor Function Of Ranbpm, Elnaz Atabakhsh

Electronic Thesis and Dissertation Repository

Ran-binding protein M (RanBPM) is an evolutionarily conserved nucleocytosolic protein that has been proposed to regulate various cellular processes, including protein stability, gene expression, receptor-mediated signalling pathways, cell adhesion, development, and apoptosis. Despite the multitude of functions attributed to RanBPM however, little is known regarding the precise mechanisms by which RanBPM executes these cellular roles. In this work, we seek to address this matter by describing functions for RanBPM in the regulation of apoptotic and pro-survival signalling pathways, and in cellular transformation.

We first identify RanBPM as a pro-apoptotic protein that regulates the activation of the intrinsic apoptotic signalling pathway …