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The Role Of The Cdk8 Kinase Module In Maintaining Proteostasis, Stephen Willis

Theses and Dissertations

The underlying etiology of numerous disease states results from perturbations in the maintenance of cellular proteostasis. Carcinogenesis relies on these perturbations to foster uncontrolled cell growth and eventual metastases, while neurodegenerative diseases are a consequence of such perturbations. Control of these processes occurs at numerous molecular levels, commonly starting with transcription. A key transcriptional complex that is involved is the CDK8 Kinase Module (CKM). The CKM is conserved from yeast to man, forming a tetrameric complex consisting of MED12, MED13, CDK8, and CCNC. The CKM has not only been implicated in a variety of cancers but also in a spectrum …

Protacs – A Novel And Rapidly Developing Field Of Targeted Protein Degradation, Hannah R. Gatley

Theses and Dissertations

There is a continued need for new technology and strategies for tackling cancer and other diseases, and within the current century a novel therapeutic strategy has emerged in the realm of targeted protein degradation called Proteolysis-Targeting Chimeras (PROTACs). This technology specifically targets and degrades disease-causing proteins via the ubiquitin-proteasome system, and has seen an explosion of research and intrigue in both academia and industry over the past two decades. The diversity of PROTAC classes based on the E3 ligase recruiting ligand and the target protein allows for a universal molecular structure that can be customized for a specific target and …

Synthetic Lectins, A Diagnostic And Prognostic Tool For Detecting Glycans In Breast Cancer, Daniel James Gordon

Theses and Dissertations

Cancer diagnostic tools have been pushed to the forefront of medical research because a person’s chance of survival is directly correlated with how early the tumor is identified and treatment is begun. In searching for the subtle differences between healthy and tumor cells, almost every type of cancer has been shown to under, over, or neo express glycans, and these changes in the glycan fingerprint can continue as the disease progresses. This provides a powerful diagnostic opportunity that’s works by screening for glycoproteins and glycosylation patterns that deviate from normal cells.

Boronic acids have a useful and tunable property in …

Characterization Of Staphylococcal Nuclease And Tudor Domain Containing Protein 1 (Snd1) As A Molecular Target In Hepatocellular Carcinoma And Non-Alcoholic Steatohepatitis, Nidhi H. Jariwala

Theses and Dissertations

CHARACTERIZATION OF STAPHYLOCOCCAL NUCLEASE AND TUDOR DOMAIN CONTAINING PROTEIN 1 (SND1) AS A MOLECULAR TARGET IN HEPATOCELLULAR CARCINOMA AND NON-ALCOHOLIC STEATOHEPATITIS

Nidhi Jariwala, PhD

A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Integrative Life Sciences

Virginia Commonwealth University, 2017

Devanand Sarkar, M.B.B.S., PhD.

Associate Professor, Department of Human and Molecular Genetics

Virginia Commonwealth University

Richmond, Virginia

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). Oncoprotein SND1 regulates gene expression at a post-transcriptional level in multiple cancers including hepatocellular carcinoma (HCC). …

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 …

Pyridinium Bis-Retinoids A2-Dopamine And A2-Cadaverine: Implications In Age-Related Macular Degeneration And Cancer, Mckenzie Ruth Pew

Theses and Dissertations

Age-related macular degeneration (AMD) is the leading cause of blindness in the United States of America. The pyridinium bis-retinoid A2-ethanolamine (A2E) has been implicated to play a role in AMD. We have observed novel pyridinium bis-retinoids through melanolipofuscin and human RPE extractions that may also play a role in the pathology of AMD. We have begun the construction of an amino-retinoid library in order to identify these ocular compounds. The compounds from the amino-retinoid library are also used in a targeted and triggered drug delivery system for treating cancer. Folic acid is coupled with the amino-retinoids to specifically target cancer …

The Role Of Sphingosine Kinase 2 In Cell Growth And Apoptosis, Heidi M. Sankala

Theses and Dissertations

Two isoforms of sphingosine kinase (SphK) catalyze the formation of sphingosine-1-phosphate (SIP). Whereas, SphKl stimulates cell growth and survival, it was found that when overexpressed in mouse NIH 3T3 fibroblasts SphK2 enhances caspase-dependent apoptosis in response to serum deprivation, independently of S1P receptors. Sequence analysis revealed that SphK2 contains a 9 amino acid motif similar to that present in BH3-only proteins. Studies showed that the BH3-only domain, catalytic activity, endoplasmic reticulum (ER) stress, and uptake of calcium by the mitochondria may all contribute to the apoptotic effects of overexpressed SphK2 in NIH 3T3 cells. Further studies in human carcinoma cells …

Role Of Mdm2 In Cell Growth Regulation, Rebecca Anne Frum

Theses and Dissertations

MDM2 has been shown to induce G0-Gl/S phase arrest. To determine the cell cycle step targeted by MDM2, flow cytometry was employed to detect induction of events during the G1-S phase transition in MDM2-arrested cells. MDM2 overexpression does not prevent expression of cyclin D, cyclin D-CDK mediated phosphorylation of Rb or cyclin E in normal, immortal or tumor-derived cells. However, MDM2 down-regulates cyclin A expression specifically in normal cells, which is associated with G1 arrest. The domain of MDM2 capable of this function is located within its N-terminal 58-109 amino acids. To down-regulate cyclin A, MDM2 requires a functional pl6/Brg …

Identification Of The Rna Cis-Elements That Interact With Srp30a To Regulate The Alternative Splicing Of Caspase 9 Pre-Mrna, Prabhat Mukerjee

Theses and Dissertations

Studies have shown that the alternative splicing of caspase 9 and the phospho-status of SR proteins, a conserved family of splicing factors, are regulated by chemotherapy and de novo ceramide via the action of protein phosphatase-1 (PP1). Two RNA splice variants are derived from the caspase 9 gene, pro-apoptotic caspase 9a and anti-apoptotic caspase 9b, via alternative splicing by either the inclusion or exclusion of an exon 3, 4, 5, and 6 cassette. In this study, the link between SR proteins and the alternative splicing of caspase 9 was established. Sequence analysis of the exon 3, 4, 5, and 6 …

Studies Of N⁵, N¹⁰-Methylene Tetrahydrofolate Reductase From Porcine Kidney And Mouse L1210-Induced Tumor Tissues, Purification And Interaction With Antifolates, David W. Jayme

Theses and Dissertations

Methylene tetrahydrofolate reductase has been purified 1000-fold from porcine kidney and 400-fold from mouse L1210-induced tumor tissue by classical methods. The enzyme preparations have been demonstrated to be essentially free of contaminating methionine synthetase and serine transhydroxymethylase activity. Studies of the kinetic properties of the kidney and tumor enzymes, with respect to the reverse reaction using N5-methyl tetrahydrofolate as the variable substrate, have indicated Km values of 2.0 and 2.4 x 10-4 M, respectively. Inhibition of this key branch point enzyme in folate metabolism by a number of antimetabolites indicates that several of these antifolate compounds exhibit enzyme inhibition superior …