Molecular Biology Commons^™

X-Linked Ubiquitin-Specific Peptidase 11 Increases Tauopathy Vulnerability In Women, Yan Yan

USF Tampa Graduate Theses and Dissertations

Women experience significantly higher tau burden and increased risk for Alzheimer’s disease (AD) than men, yet the underlying mechanism for this vulnerability has not been explained. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that X-linked ubiquitin specific peptidase 11 (USP11) augments pathological tau aggregation via tau deubiquitination initiated at lysine-281. Removal of ubiquitin provides access for enzymatic tau acetylation at lysines 281 and 274. USP11 escapes complete X-inactivation, and female mice and people both exhibit higher USP11 levels than males. Genetic elimination of usp11 in a tauopathy mouse model preferentially …

Enhancing Therapeutic Approaches For Melanoma Patients Targeting Epigenetic Modifiers., Maria Gracia-Hernandez, Zuleima Munoz, Alejandro Villagra

Biochemistry and Molecular Medicine Faculty Publications

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and …

Lysine 53 Acetylation Of Cytochrome C In Prostate Cancer: Warburg Metabolism And Evasion Of Apoptosis, Viktoriia Bazylianska, Hasini A. Kalpage, Junmei Wan, Asmita Vaishnav, Gargi Mahapatra, Alice A. Turner, Dipanwita Dutta Chowdhury, Katherine Kim, Paul T. Morse, Icksoo Lee, Joseph S. Brunzelle, Lisa Polin, Prabal Subedi, Elisabeth I. Heath, Izabela Podgorski, Katrin Marcus, Brian Fp Edwards, Maik HüTtemann

Biochemistry and Molecular Biology Faculty Publications

Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the …

Implications Of Lysine Acetylation On The Enzymes Of The Tca Cycle, Sumana Venkat

Graduate Theses and Dissertations

The tricarboxylic acid (TCA) cycle is a central route for the energy production via oxidative phosphorylation and is ubiquitous throughout nature. Apart from playing a major role in energy provision, it is also essential for a wide range of physiological functions in any organism. Although an increasing emphasis is laid on the interlinking role of the cycle, its regulation and control are less very less understood. As the field progresses, the consequences of TCA cycle anomalies are shown to be tied to various cancers and other disorders. The matter becomes more complex when considering the varying functions of the isozymes …

Epigenetic Regulation Of Hormone Action In The Red Flour Beetle, Tribolium Castaneum (Herbst), Smitha George

Theses and Dissertations--Entomology

Hormones are the chemical communication signaling molecules released into the body fluid to stimulate target cells of multicellular organisms. Two major hormones, ecdysteroids (20-hydroxyecdysone, 20E) and juvenile hormones (JH), regulate a wide variety of physiological and developmental processes in insects. Therefore, hormones have been extensively studied and are attractive targets for the development of target-specific insect control methods. Recent studies suggest that epigenetics adds another layer of regulation to explain multiple functions of the same circulating hormone in different tissues and at various time points. In my dissertation, I focused on a major post-translational modification, ‘acetylation,’ to elucidate the epigenetic …

Global Acetylation Dynamics In The Heat Shock Response Of Saccharomyces Cerevisiae, Rebecca E. Hardman

Graduate Theses and Dissertations

All organisms face a constant barrage of environmental stresses. Single-cell organisms such as Saccharomyces cerevisiae, or common Baker’s yeast, must rely solely on cellular responses in order to survive. This response must occur in a rapid and highly coordinated manner to quickly inhibit all unnecessary processes and shuttle all available resources to those necessary for survival. One method that cells utilize for rapid protein regulation is the use of post-translational modifications. Enzymes within the cell add or remove a variety of chemical modifications, thus altering the local chemical environment of a protein. This creates a conformational change in the protein …

Divergent Transcriptional Regulation Of Suppressors Of Cytokine Signaling Genes In Adipocytes, Paula Mota De Sa

LSU Doctoral Dissertations

The Janus Kinase - Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway transduces several signals crucial for development and homeostasis. Suppressors of cytokine signaling (SOCS) proteins control JAK-STAT signaling via a negative feedback loop. The transcription factor STAT5 is known to play a significant role in fat cell development and function, and several studies suggest that acetylation may affect STAT5 transcriptional activity. To test this hypothesis, we treated 3T3-L1 adipocytes with growth hormone (GH) to activate STAT5 in the presence or absence of histone deacetylase (HDAC) inhibitors. STAT5 acetylation levels were low in adipocytes and mostly unchanged by the …

Targeting Sphingosine Kinase 2 As A Treatment For Cholangiocarcinoma, Anthony D. Stillman

Theses and Dissertations

Cholangiocarcinoma (CCA) has a high mortality rate and its occurrence is rising. This increase prompts the need for improved CCA treatments. Studies have suggested that CCA is highly reliant on the sphingosine-1-phosphate-receptor-2 (S1PR2) and sphingosine kinase 2 (SphK2). Recently, a competitive SphK2 inhibitor, ABC294640, has been approved for clinical trial. ABC294640 has the potential to treat CCA, which is support by a phase I clinical study that was able to temporarily treat a patient suffering from metastasized CCA with ABC294640. To determine the viability of ABC294640 as a treatment for CCA, this study focused on determining the effects of ABC294640 …

Functional Characterization Of O-Acetyltransferase Wssi: Role In Bacterial Cellulose Acetylation Of Achromobacter Insuavis And Pseudomonas Fluorescens, Alysha Burnett

Theses and Dissertations (Comprehensive)

Cellulose biofilms consist of a community of bacterial cells encased in a self-produced matrix of polymers (e.g. exopolysaccharides, such as cellulose) that facilitate a firm adherence to surfaces. The acetylation (addition of an acetyl group on carbohydrates) is crucial in virulence; thereby in some cases allowing opportunistic bacteria to cause harmful diseases. Pertaining to this research, the wrinkly spreader (WS) genotype of Pseudomonas fluorescens colonizes the air-liquid interface on food, water sources and human tissue to form a robust biofilm with the ability to spread across surfaces. The composition of this biofilm largely consists of bacterial cellulose polymers …

Investigation Of Alcohol-Induced Changes In Hepatic Histone Modifications Using Mass Spectrometry Based Proteomics, Crystina Leah Kriss

USF Tampa Graduate Theses and Dissertations

Alcohol liver disease (ALD) is a major health concern throughout the world. Currently, in the United States, 17 million people suffer from alcoholism, of which 1.4 million people are receiving treatment [1, 2]. The link between ethanol metabolism, reactive oxygen species (ROS) and liver injury in ALD has been well characterized over the last couple decades [3-10]. Ethanol metabolism relies on the availability of the cofactor NAD+ for the oxidation of ethanol into acetate, consequently causing alterations in redox potential. Redox dysfunction within the mitochondria can affect multiple pathways important in maintaining cellular homeostasis. Chapter 1 provides an introduction to …

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

Dissertations & 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. …

Regulation Of Alteration/Deficiency In Activation 3 (Ada3) By Acetylation And Its Role In Cell Cycle Regulation And Oncogenesis, Shashank Srivastava

Theses & Dissertations

The ADA3 (Alteration/Deficiency in Activation 3) protein is a transcriptional adaptor protein that was initially discovered as a component of several HAT (Histone Acetyltransferase) complexes, the enzyme complex responsible for histone acetylation, which is a prerequisite for transcription. Earlier the studies from Dr. Band’s laboratory and that of others’ have deciphered a crucial role of ADA3 in cell cycle regulation (both through G₁/S and G₂/M phase transitions) and in maintaining the genomic stability.

While our laboratory investigated the mechanism behind the role of ADA3 in G₁/S transition, the same remained unknown for G_{2 …}

Tubulin Post-Translational Modifications Are Altered By Changes In Actin-Myosin Contractility In Non-Muscle Cells, James Mcgee

Honors Theses

All cells regulate their contractility by the interaction of actin and myosin. In non-muscle cells, however, this interaction is regulated by rho, a GTPase, which is the upstream effector for multiple pathways. Cell contractility increases when rho is active, and prior research has shown the depolymerization of microtubules (MTs) activates rho. Microtubules play a role in many cellular functions and it is thought that either associations with MT-associated proteins and/or post-translational modifications to tubulin regulate MT functions. Numerous post-translational modifications (PTMs) to microtubules have been identified, but their roles are not well understood. A possible relationship between changes in cell …

The Effect Of Posttranslational Modifications On Protein Aggregation, Morphology, And Toxicity, Mu Yang

Dissertations, Master's Theses and Master's Reports

Proteins are one of the most versatile macromolecules in the biological system. The function or activity of a protein highly depends on its 3D native structure. However, under stress, they are at risk of misfolding/aggregation, leading to formation of structures that can indicate loss of function or gain of toxicity. In severe cases, protein aggregation can result in many diseases, including neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis. Due to the heterogeneous nature of cellular environment and protein molecules, mechanism of in vivo folding and related toxicity still remains elusive. To have a better understanding of …

Post-Translational Control Of Retinoblastoma Protein Phosphorylation, Paul M. Stafford

Electronic Thesis and Dissertation Repository

The retinoblastoma tumor suppressor protein (pRB) functions through multiple mechanisms to serve as a tumor suppressor. pRB has been well characterized to be inactivated through phosphorylation by CDKs. pRB dephosphorylation and activation is a much less characterized aspect of pRB function. In this thesis, I detail work to study the post translational control of pRB phosphorylation. Here I present work detailing efforts to generate a gene targeted mouse which disrupts PP1 binding to the C-terminus of pRB, allowing for detailed study of the mechanisms of pRB dephosphorylation. This work also details an examination of acetylation in the C-terminus of pRB, …

Characterization Of A Putative Sir2 Like Deacetylase And Its Role In Sabp2 Dependent Salicylic Acid Mediated Pathways In Plant, Md I. Haq

Electronic Theses and Dissertations

Salicylic Acid Binding Protein2 (SABP2) is an enzyme known to play important role in SA mediated pathway. SBIP-428 (SABP2 Interacting Protein-428), a SIR2 like deacetylase, has been found to interact with SABP2. We demonstrate that SBIP-428 functions as a Sirtuin deacetylase. We show that SBIP-428 itself is lysine acetylated. Interactions of a SBIP-428 with SABP2 also raised the possibility of SABP2 itself being lysine acetylated. The recombinant purified SABP2 or native partially purified SABP2 displayed no acetylation. In response to TMV infection, the expression of SBIP-428 was down regulated at 48 hpi. In addition, SBIP-428 was up regulated in plant …

The Role Of Cyp33 In Mll Mediated Gene Repression, Steven D. Poppen

Dissertations

Mixed Lineage Leukemia (MLL) is a multidomain protein whose gene is translocated in a subset of AML leukemias. Translocation of the MLL gene is present in approximately five percent of adult acute leukemias and ten percent of pediatric leukemias (Daser, A 2004, Look, A 1997, Huret, J 2001) Patients presenting in the clinic at the time of diagnosis with an MLL fusion have been shown to respond poorly to treatment and have a worse prognosis than matched wild type MLL patients (Rubnitz, J 1994, Rubnitz, J 1999). Novel therapies therefore are needed in order to more effectively treat patients with …

Understanding The Role Of Histones During Chromosome Segregation: A Study Of The Effects Of Histone Gene Dosage In Saccharomyces Cerevisiae, Rebecca Leigh Danforth

Graduate Theses and Dissertations

Chromatin plays a role in all cellular functions that involve DNA. These include, but are not limited to replication, recombination, transcription, and chromosome segregation. Chromosome segregation is an extremely well conserved cellular process and is essential for maintaining the genetic integrity of a cell. There is very strong evidence indicating that chromatin structure is critical for maintaining the fidelity of chromosome transmission, but its specific role(s) in this process remains unclear. Chromatin is comprised of arrays of nucleosomes that serve to compact DNA. These nucleosomes consist of 146 bp of DNA that is wrapped around a histone octamer; two each …