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2017

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Articles 1 - 30 of 451

Full-Text Articles in Molecular Biology

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres Dec 2017

Serine-Dependent Sphingolipid Synthesis Is A Metabolic Liability Of Aneuploid Cells, Sunyoung Hwang, H. Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Schevchenko, Robert C. Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M. Torres

University of Massachusetts Medical School Faculty Publications

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness ...


Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers Dec 2017

Reconciling Contradictory Findings: Glucose Transporter 1 (Glut1) Functions As An Oligomer Of Allosteric, Alternating Access Transporters, Kenneth P. Lloyd, Ogooluwa A. Ojelabi, Julie K. De Zutter, Anthony Carruthers

UMass Metabolic Network Publications

Recent structural studies suggest that glucose transporter 1 (GLUT1)-mediated sugar transport is mediated by an alternating access transporter that successively presents exofacial (e2) and endofacial (e1) substrate-binding sites. Transport studies, however, indicate multiple, interacting (allosteric), and co-existent, exo- and endofacial GLUT1 ligand-binding sites. The present study asks whether these contradictory conclusions result from systematic analytical error or reveal a more fundamental relationship between transporter structure and function. Here, homology modeling supported the alternating access transporter model for sugar transport by confirming at least four GLUT1 conformations, the so-called outward, outward-occluded, inward-occluded, and inward GLUT1 conformations. Results from docking analysis ...


Transcriptome-Wide Analysis Of Roles For Transfer Rna Modifications In Translational Regulation, Hsin-Jung Chou Dec 2017

Transcriptome-Wide Analysis Of Roles For Transfer Rna Modifications In Translational Regulation, Hsin-Jung Chou

GSBS Dissertations and Theses

Covalent nucleotide modifications in RNAs affect numerous biological processes, and novel functions are continually being revealed even for well-known modifications. Among all RNA species, transfer RNAs (tRNAs) are highly enriched with diverse modifications, which are known to play roles in decoding and tRNA stability, charging, and cellular trafficking. However, studies of tRNA modifications have been limited in a small scale and performed by groups with different methodologies. To systematically compare the functions of a large set of noncoding RNA modifications in translational regulation, I carried out ribosome profiling in 57 budding yeast mutants lacking nonessential genes involved in tRNA modifications ...


Characterization Of Calcium Homeostasis Parameters In Trpv3 And Cav3.2 Double Null Mice, Aujan Mehregan Dec 2017

Characterization Of Calcium Homeostasis Parameters In Trpv3 And Cav3.2 Double Null Mice, Aujan Mehregan

Masters Theses

In mammals, calcium influx is required for oocyte maturation and egg activation, as it supports the persistent calcium oscillations induced by fertilization. These oscillations are required for the initiation of embryo development. The molecular identities of the plasma membrane calcium-permeant channels that underlie calcium influx are not established. Among these channels, Transient Receptor Potential Vanilloid, member 3 (TRPV3) allows divalent cations, namely strontium (Sr2+) and calcium (Ca2+) with high permeability, into cells, and its expression pattern seems to predict an essential role in the initiation of development. Another channel that was identified to be expressed in oocytes/eggs ...


Dna Base Excision Repair And Double Strand Break Repair In Human Fibroblast, Mingyang Li Dec 2017

Dna Base Excision Repair And Double Strand Break Repair In Human Fibroblast, Mingyang Li

LSU Doctoral Dissertations

In eukaryotes, DNA repair mechanisms detect and repair damaged DNA. DNA damage is primarily caused by a variety of exogenous and endogenous sources. Several types of damage to DNA are repaired by different kinds of DNA repair pathways. This dissertation focused on repair of N-methylpurines (NMPs) and double-strand breaks (DSBs) in human fibroblasts.

NMPs, including N7-methylguanine (7MeG) and N3-methyladenine (3MeA), can be induced by environmental methylating agents (e.g. the soil fumigant methyl bromide), chemotherapeutics (e.g. nitrogen mustards), and natural cellular methyl donors like S-adenosylmethionine. In human cells, NMPs are repaired by the multi-step ...


Identification Of Factors Involved In 18s Nonfunctional Ribosomal Rna Decay And A Method For Detecting 8-Oxoguanosine By Rna-Seq, Kelly A. Limoncelli Dec 2017

Identification Of Factors Involved In 18s Nonfunctional Ribosomal Rna Decay And A Method For Detecting 8-Oxoguanosine By Rna-Seq, Kelly A. Limoncelli

GSBS Dissertations and Theses

The translation of mRNA into functional proteins is essential for all life. In eukaryotes, aberrant RNAs containing sequence features that stall or severely slow down ribosomes are subject to translation-dependent quality control. Targets include mRNAs encoding a strong secondary structure (No-Go Decay; NGD) or stretches of positively-charged amino acids (Peptide-dependent Translation Arrest/Ribosome Quality Control; PDTA/RQC), mRNAs lacking an in-frame stop codon (Non-Stop Decay; NSD), or defective 18S rRNAs (18S Nonfunctional rRNA Decay; 18S NRD). Previous work from our lab showed that the S. cerevisiae NGD factors DOM34 and HBS1, and PDTA/RQC factor ASC1, all participate in the ...


Mechanistic Insights Into The Regulation Of Mitochondrial Fission By Cyclin C, Vidyaramanan Ganesan, Katrina F Cooper, Randy Strich Dec 2017

Mechanistic Insights Into The Regulation Of Mitochondrial Fission By Cyclin C, Vidyaramanan Ganesan, Katrina F Cooper, Randy Strich

School of Osteopathic Medicine Faculty Scholarship

Cyclin C is a component of the mediator complex of RNA polymerase II that localizes to the nucleus under normal conditions. In response to stress, cyclin C translocates to the cytosol and mitochondria and mediates stress‐induced mitochondrial fission and apoptosis. The molecular mechanisms by which cyclin C induces mitochondrial fission are unknown. Using in vitro experimental approaches, we sought to investigate the mechanistic basis of cyclin C mediated mitochondrial fission.


The Role Of Mapk And Scf In The Destruction Of Med13 In Cyclin C Mediated Cell Death, David C Stieg, Stephen D Willis, Joseph Scuorzo, Mia Song, Vidyaramanan Ganesan, Randy Strich, Katrina F Cooper Dec 2017

The Role Of Mapk And Scf In The Destruction Of Med13 In Cyclin C Mediated Cell Death, David C Stieg, Stephen D Willis, Joseph Scuorzo, Mia Song, Vidyaramanan Ganesan, Randy Strich, Katrina F Cooper

School of Osteopathic Medicine Faculty Scholarship

In response to stress, the yeast1 and mammalian2 cyclin C translocate from the nucleus to the cytoplasm, where it associates with the GTPase Drp1/Dnm1 to drive mitochondrial fragmentation and apoptosis. Therefore, the decision to release cyclin C represents a key life or death decision. In unstressed cells, the cyclin C‐Cdk8 kinase regulates transcription by associating with the Mediator of RNA polymerase II. We previously reported that the Mediator component Med13 anchors cyclin C in the nucleus3. Loss of Med13 function leads to constitutive cytoplasmic localization of cyclin C, resulting in fragmented mitochondria, hypersensitivity to stress ...


Translocation Of Cyclin C During Oxidative Stress Is Regulated By Interactions With Multiple Trafficking Proteins, Daniel G J Smethurst, Katrina F Cooper, Randy Strich Dec 2017

Translocation Of Cyclin C During Oxidative Stress Is Regulated By Interactions With Multiple Trafficking Proteins, Daniel G J Smethurst, Katrina F Cooper, Randy Strich

School of Osteopathic Medicine Faculty Scholarship

Eukaryotic cells take cues from their environment and interpret them to enact a response. External stresses can produce a decision between adjusting to behaviors which promote surviving the stress, or enacting a cell death program. The decision to undergo programmed cell death (PCD) is controlled by a complex interaction between nuclear and mitochondrial signals. The mitochondria are highly dynamic organelles that constantly undergo fission and fusion. However, a dramatic shift in mitochondrial morphology toward fission occurs early in the PCD process. We have identified the transcription factor cyclin C as the biochemical trigger for stress‐induced mitochondrial hyper‐fragmentation in ...


Snf1 Dependent Destruction Of Med13 Is Required For Programmed Cell Death Following Oxidative Stress In Yeast, Stephen D Willis, David C Stieg, R. Shah, Randy Strich, Katrina F Cooper Dec 2017

Snf1 Dependent Destruction Of Med13 Is Required For Programmed Cell Death Following Oxidative Stress In Yeast, Stephen D Willis, David C Stieg, R. Shah, Randy Strich, Katrina F Cooper

School of Osteopathic Medicine Faculty Scholarship

All eukaryotic cells, when faced with unfavorable environmental conditions, have to decide whether to mount a survival or cell death response. The conserved cyclin C and its kinase partner Cdk8 play a key role in this decision. Both are members of the Cdk8 kinase module that, along with Med12 and Med13, associate with the core mediator complex of RNA polymerase II. In S. cerevisiae, oxidative stress triggers Med13 destruction1, which thereafter releases cyclin Ci nto the cytoplasm. Cytoplasmic cyclin C associates with mitochondria where it induces hyper-fragmentation and programmed cell death2. This suggests a model in which oxidative ...


9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov Dec 2017

9-Aminoacridine Inhibits Ribosome Biogenesis And Synergizes With Cytotoxic Drugs To Induce Selective Killing Of P53-Deficient Cells, Leonid Anikin, Dimitri G Pestov

School of Osteopathic Medicine Faculty Scholarship

Common cancer treatments target rapidly dividing cells and do not discriminate between cancer and normal host cells. One approach to mitigating negative side‐effects of cancer treatment is to temporarily arrest cell cycle progression and thus protect normal cells during cytotoxic treatments, a concept called cyclotherapy. We recently proposed that transient inhibition of post‐transcriptional steps of ribosome biogenesis (RBG) can be used to selectively arrest p53‐positive host cells and not p53‐null cancer cells. In this study, we investigated whether cytoprotective RBG inhibition can be achieved through small molecule treatment.


Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego Dec 2017

Metabolic Reprogramming Of Pancreatic Ductal Adenocarcinoma Cells In Response To Chronic Low Ph Stress, Jaime Abrego

Theses & Dissertations

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of all cancers with a 5-year survival rate of only 8.2%. This is because PDAC is diagnosed in its advanced stages and is characterized by radio and chemotherapy resistance. Aggressiveness of PDAC tumors is attributed to its high metabolic phenotype, which is characterized by increased glycolysis rate and lactate secretion, while oxidative metabolism is reduced. These metabolic features are required to fulfill the biosynthetic demands of proliferating PDAC cells. However, this increase in metabolic activity results in acidification of the extracellular space because the dense fibrotic stroma of PDAC tumors ...


Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam Dec 2017

Role Of Ezrin In Colorectal Cancer Cell Survival Regulation, Premila Leiphrakpam

Theses & Dissertations

Colorectal cancer (CRC) is the second most common cause of cancer related deaths in the United States, mainly due to metastasis to the distant organ sites. However, the molecular basis of CRC metastasis is poorly understood. Therefore, identification and characterization of novel potential anti-cancer therapeutic targets CRC is of urgent need. Utilizing a 2D-DIGE proteomics approach ezrin was identified as a protein that is differentially expressed between primary colon tumors xenografts, orthotopically implanted in athymic nude mice, and corresponding and liver metastatic deposits. Ezrin, a cytoskeletal protein belonging to the ezrin–radixin–moesin (ERM) family plays important roles in cell ...


Effects Of Crude Oil On Tumor Suppressor P53 Polymorphisms In Laboratory-Exposed Atlantic Killifish, Fundulus Heteroclitus, Allison Margaret Nadler Dec 2017

Effects Of Crude Oil On Tumor Suppressor P53 Polymorphisms In Laboratory-Exposed Atlantic Killifish, Fundulus Heteroclitus, Allison Margaret Nadler

Seton Hall University Dissertations and Theses (ETDs)

Polycyclic aromatic hydrocarbons (PAHs), constituents of crude oil, are implicated as a potent source of adverse toxicological effects on living organisms. To model the effects of PAHs in response to environmental oil spill disasters a species of killifish (Fundulus heteroclitus) was captured and exposed to crude oil in a laboratory-controlled setting. Over a period of 7 days, fish were dosed with crude oil by gavage, culled, and organs were harvested for analysis. Excitation-emission matrix spectroscopy (EEMS) of gall bladder tissue homogenates was used to verify exposure. Effects of PAHs on the p53 gene were evaluated as an indicator of genotoxicity ...


Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper Dec 2017

Attaching-And-Effacing Pathogens Exploit Junction Regulatory Activities Of N-Wasp And Snx9 To Disrupt The Intestinal Barrier, John J. Garber, Emily M. Mallick, Karen M. Scanlon, Jerrold R. Turner, Michael S. Donnenberg, John M. Leong, Scott B. Snapper

Open Access Articles

Background and Aims: Neural Wiskott-Aldrich Syndrome protein (N-WASP) is a key regulator of the actin cytoskeleton in epithelial tissues and is poised to mediate cytoskeletal-dependent aspects of apical junction complex (AJC) homeostasis. Attaching-and-effacing (AE) pathogens disrupt this homeostasis through translocation of the effector molecule early secreted antigenic target-6 (ESX)-1 secretion-associated protein F (EspF). Although the mechanisms underlying AJC disruption by EspF are unknown, EspF contains putative binding sites for N-WASP and the endocytic regulator sorting nexin 9 (SNX9). We hypothesized that N-WASP regulates AJC integrity and AE pathogens use EspF to induce junction disassembly through an N-WASP- and SNX9-dependent ...


Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo Dec 2017

Loss Of The Cone-Enriched Caspase-7 Does Not Affect Secondary Cone Death In Retinitis Pigmentosa, Aditya Venkatesh, Shun-Yun Cheng, Claudio Punzo

University of Massachusetts Medical School Faculty Publications

Purpose: The apoptotic mechanisms responsible for secondary cone death in retinitis pigmentosa (RP) remain largely unknown. The cone-enriched apoptotic protease caspase-7 (Casp7) is thought to be triggered by endoplasmic reticulum (ER) stress and plays a pivotal role in mice deficient in the cone cyclic nucleotide-gated channels, a deficiency that causes achromatopsia in humans and in mice with autosomal dominant rhodopsin mutations, in particular the T17M mutation. Thus, we tested in two mouse models of RP whether the cone-enriched Casp7 plays a role during secondary cone death.

Methods: Casp7 knockout mice were crossed to two different RP mouse models with significantly ...


Regulation Of Gene Expression By Rna Binding Proteins And Micrornas, Kyle Cottrell Dec 2017

Regulation Of Gene Expression By Rna Binding Proteins And Micrornas, Kyle Cottrell

Arts & Sciences Electronic Theses and Dissertations

Regulation of gene expression is essential to life. Post-transcriptional regulation of gene expression is a complex process with many inputs that lead to changes in localization, translation and stability of mRNAs. The translation and stability of many mRNAs is regulated by cis-elements, such as mRNA-structure or codon optimality; and by trans-acting factors such as RBPs and miRNAs. Here I report on the complex interactions between RBPs, miRNAs and characteristics of their target mRNAs in respect to effects on translation and RNA stability.

Using a reporter based approach we studied modulation of microRNA-mediated repression by various mRNA characteristics. We observed the ...


The Regulation Of Extracellular Amyloid-Β Levels By Ionotropic Glutamatergic Transmission In An Alzheimer’S Disease Mouse Model, Jane Cecelia Hettinger Dec 2017

The Regulation Of Extracellular Amyloid-Β Levels By Ionotropic Glutamatergic Transmission In An Alzheimer’S Disease Mouse Model, Jane Cecelia Hettinger

Arts & Sciences Electronic Theses and Dissertations

Brain extracellular concentration of the peptide amyloid-β (Aβ) is a major contributor to Alzheimer’s disease (AD) pathogenesis. High Aβ levels in the extracellular space precipitate aggregation of the peptide into soluble and insoluble toxic species. This process begins decades before cognitive impairment and triggers the cascade of pathology that eventually leads to AD. Synaptic activity is key to the regulation of extracellular Aβ levels. Presynaptic activity drives the production of Aβ, while postsynaptic receptor activation exhibits more nuanced regulation. For example, high levels of NMDA receptor (NMDA-R) activation have been shown to decrease Aβ production through the extracellular signal-regulated ...


Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel Dec 2017

Hepatic Dysfunction Caused By Consumption Of A High-Fat Diet, Anthony R. Soltis, Norman J. Kennedy, Xiaofeng Xin, Feng Zhou, Scott B. Ficarro, Yoon Sing Yap, Bryan J. Matthews, Douglas A. Lauffenburger, Forest M. White, Jarrod A. Marto, Roger J. Davis, Ernest Fraenkel

University of Massachusetts Medical School Faculty Publications

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver ...


Structural Determination Of The Broadly Reactive Anti-Ighv1-69 Anti-Idiotypic Antibody G6 And Its Idiotope, Yuval Avnir, Kristina L. Prachanronarong, Shurong Hou, Brendan J. Hilbert, Markus-Frederik Bohn, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Nese Kurt Yilmaz, Celia A. Schiffer, Wayne A. Marasco Dec 2017

Structural Determination Of The Broadly Reactive Anti-Ighv1-69 Anti-Idiotypic Antibody G6 And Its Idiotope, Yuval Avnir, Kristina L. Prachanronarong, Shurong Hou, Brendan J. Hilbert, Markus-Frederik Bohn, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang, Nese Kurt Yilmaz, Celia A. Schiffer, Wayne A. Marasco

Schiffer Lab Publications

The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in several B cell malignancies and autoimmune diseases. G6 is an anti-idiotypic monoclonal Ab that selectively binds to IGHV1-69 heavy chain germline gene 51p1 alleles that have been implicated in these Ab responses and disease processes. Here, we determine the co-crystal structure of humanized G6 (hG6.3) in complex with anti-influenza hemagglutinin stem-directed broadly neutralizing Ab D80. The core of the hG6.3 idiotope is a continuous string of CDR-H2 ...


The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio Dec 2017

The Alpha6beta4 Integrin Promotes Resistance To Ferroptosis, Caitlin W. Brown, John J. Amante, Hira Lal Goel, Arthur M. Mercurio

UMass Metabolic Network Publications

Increases in lipid peroxidation can cause ferroptosis, a form of cell death triggered by inhibition of glutathione peroxidase 4 (GPX4), which catalyzes the reduction of lipid peroxides and is a target of ferroptosis inducers, such as erastin. The alpha6beta4 integrin protects adherent epithelial and carcinoma cells from ferroptosis induced by erastin. In addition, extracellular matrix (ECM) detachment is a physiologic trigger of ferroptosis, which is evaded by alpha6beta4. The mechanism that enables alpha6beta4 to evade ferroptosis involves its ability to protect changes in membrane lipids that are proferroptotic. Specifically, alpha6beta4-mediated activation of Src and STAT3 suppresses expression of ACSL4, an ...


One-Step Hot Formamide Extraction Of Rna From Saccharomyces Cerevisiae, Daniel Shedlovskiy, Natalia Shcherbik, Dimitri G Pestov Dec 2017

One-Step Hot Formamide Extraction Of Rna From Saccharomyces Cerevisiae, Daniel Shedlovskiy, Natalia Shcherbik, Dimitri G Pestov

School of Osteopathic Medicine Faculty Scholarship

Current methods for isolating RNA from budding yeast require lengthy and laborious steps such as freezing and heating with phenol, homogenization with glass beads, or enzymatic digestion of the cell wall. Here, extraction with a solution of formamide and EDTA was adapted to isolate RNA from whole yeast cells through a rapid and easily scalable procedure that does not require mechanical cell lysis, phenol, or enzymes. RNA extracted with formamide-EDTA can be directly loaded on gels for electrophoretic analysis without alcohol precipitation. A simplified protocol for downstream DNase treatment and reverse transcription reaction is also included. The formamide-EDTA extraction of ...


Determination Of The Effects Of Different Maillard Reaction Products On The Taxonomic Composition Of The Gut Microbiota, Nesreen Hamdan Aljahdali Dec 2017

Determination Of The Effects Of Different Maillard Reaction Products On The Taxonomic Composition Of The Gut Microbiota, Nesreen Hamdan Aljahdali

Theses and Dissertations

The Maillard Reaction (MR) is a non-enzymatic chemical reaction which results in linkage between the amino group of amino acids and the carbonyl group of reduced sugars. This reaction generates Maillard reaction products (MRPs) which are not present naturally in foods, and are responsible for a range of colors, odors, flavors, and other sensory properties. Conflicting reports of MRPs impacts on human health are probably due to the fact that bioconversion of these digestible molecules by the gut microbiota has been marginally taken into account. This study aimed to determine the effects of different MRPs on rodent’s gut microbiota ...


Understanding Intracellular Redox Regulation In Methanogens: Characterization Of The Components And Targets Of The Nadph-Dependent Thioredoxin System From Methanosarcina Acetivorans, Addison Clark Mccarver Dec 2017

Understanding Intracellular Redox Regulation In Methanogens: Characterization Of The Components And Targets Of The Nadph-Dependent Thioredoxin System From Methanosarcina Acetivorans, Addison Clark Mccarver

Theses and Dissertations

All cells have a reduced intracellular environment. In the presence of oxygen, the non-specific oxidation of intracellular components leads to the production of reactive oxygen species (ROS) within cells leading to oxidative stress. During oxidative stress labile cofactors (e.g. Fe-S clusters) are lost and deleterious disulfide bonds are formed within proteins. Intracellular redox maintenance systems are used to direct reducing equivalents towards the repair of oxidatively-damaged proteins. The thioredoxin system is the ubiquitous intracellular redox system, found in virtually all species. The canonical thioredoxin system is comprised of a NADPH-dependent thioredoxin reductase (TrxR) that functions to reduced thioredoxin (Trx ...


Molecular Architectures Of Benzoic Acid-Specific Type Iii Polyketide Synthases, Charles Stewart Jr., Kate Woods, Greg Macias, Andrew C. Allan, Roger P. Hellens, Joseph P. Noel Dec 2017

Molecular Architectures Of Benzoic Acid-Specific Type Iii Polyketide Synthases, Charles Stewart Jr., Kate Woods, Greg Macias, Andrew C. Allan, Roger P. Hellens, Joseph P. Noel

Office of Biotechnology Publications

Biphenyl synthase and benzophenone synthase constitute an evolutionarily distinct clade of type III polyketide synthases (PKSs) that use benzoic acid-derived substrates to produce defense metabolites in plants. The use of benzoyl-CoA as an endogenous substrate is unusual for type III PKSs. Moreover, sequence analyses indicate that the residues responsible for the functional diversification of type III PKSs are mutated in benzoic acid-specific type III PKSs. In order to gain a better understanding of structure–function relationships within the type III PKS family, the crystal structures of biphenyl synthase from Malus × domestica and benzophenone synthase from Hypericum androsaemum were compared with ...


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

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences 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 ...


Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry Dec 2017

Characterization Of Notch1 And Pi3k-Pten-Akt/Mtor Pathway Interaction In Head And Neck Squamous Cell Carcinoma, Kyriante' Henry

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)

Head and neck squamous cell carcinoma (HNSCC) affects various mucosal sites of the upper aerodigestive tract, including the nasal and oral cavities, the nasopharynx, and the oropharynx. More than five hundred thousand new cases of HNSCC occurred in 2011 alone, with 50,000 reported cases in the United States. This trend made HNSCC the seventh most common non-skin cancer worldwide (Ferlay et al., 2015). Although significant epidemiological and pathological advancements have been made, survival rates have not improved much over the last 40 years, leaving a mortality rate that remains at approximately 50%. An unbiased drug screen demonstrated that HNSCC ...


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

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences 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

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences 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 ...


Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano Dec 2017

Temporal Regulation Of Chromatin During Myoblast Differentiation, Akihito Harada, Yasuyuki Ohkawa, Anthony N. Imbalzano

UMass Metabolic Network Publications

The commitment to and execution of differentiation programmes involves a significant change in gene expression in the precursor cell to facilitate development of the mature cell type. In addition to being regulated by lineage-determining and auxiliary transcription factors that drive these changes, the structural status of the chromatin has a considerable impact on the transcriptional competence of differentiation-specific genes, which is clearly demonstrated by the large number of cofactors and the extraordinary complex mechanisms by which these genes become activated. The terminal differentiation of myoblasts to myotubes and mature skeletal muscle is an excellent system to illustrate these points. The ...