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Articles 1 - 30 of 304

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

Selective Inhibition Of N-Linked Glycosylation Impairs Receptor Tyrosine Kinase Processing, Elsenoor Klaver, Peng Zhao, Melanie May, Heather Flanagan-Steet, Hudson H. Freeze, Reid Gilmore, Lance Wells, Joseph Contessa, Richard Steet Jun 2019

Selective Inhibition Of N-Linked Glycosylation Impairs Receptor Tyrosine Kinase Processing, Elsenoor Klaver, Peng Zhao, Melanie May, Heather Flanagan-Steet, Hudson H. Freeze, Reid Gilmore, Lance Wells, Joseph Contessa, Richard Steet

Open Access Articles

Global inhibition of N-linked glycosylation broadly reduces glycan occupancy on glycoproteins, but identifying how this inhibition functionally impacts specific glycoproteins is challenging. This limits our understanding of pathogenesis in the congenital disorders of glycosylation (CDG). We used selective exo-enzymatic labeling of cells deficient in the two catalytic subunits of oligosaccharyltransferase - STT3A and STT3B - to monitor the presence and glycosylation status of cell surface glycoproteins. We show reduced abundance of two canonical tyrosine receptor kinases - the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) - at the cell surface in STT3A-null cells, due to decreased N-linked glycan site occupancy and proteolytic ...


Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen May 2019

Adipocyte Acly Facilitates Dietary Carbohydrate Handling To Maintain Metabolic Homeostasis In Females, Sully Fernandez, John M. Viola, Annmarie Torres, Martina Wallace, Sophie Trefely, Steven Zhao, Hayley C. Affronti, Jivani M. Gengatharan, David A. Guertin, Nathaniel W. Snyder, Christian M. Metallo, Kathryn E. Wellen

Open Access Articles

Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes in response to carbohydrate consumption and generates acetyl-coenzyme A (CoA) for both lipid synthesis and acetylation reactions. Here, we investigate the role of ACLY in the metabolic and transcriptional responses to carbohydrates in adipocytes and unexpectedly uncover a sexually dimorphic function in maintaining systemic metabolic homeostasis. When fed a high-sucrose diet, Acly(FAT-/-) females exhibit a lipodystrophy-like phenotype, with minimal fat accumulation, insulin resistance, and hepatic lipid accumulation, whereas Acly(FAT-/-) males have only mild metabolic phenotypes. We find that ACLY is ...


Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani Apr 2019

Ouabain Enhances Cell-Cell Adhesion Mediated By Beta1 Subunits Of The Na(+),K(+)-Atpase In Cho Fibroblasts, Claudia Andrea Vilchis-Nestor, Maria Luisa Roldan, Angelina Leonardi, Juan G. Navea, Teresita Padilla-Benavides, Liora Shoshani

Open Access Articles

Adhesion is a crucial characteristic of epithelial cells to form barriers to pathogens and toxic substances from the environment. Epithelial cells attach to each other using intercellular junctions on the lateral membrane, including tight and adherent junctions, as well as the Na(+),K(+)-ATPase. Our group has shown that non-adherent chinese hamster ovary (CHO) cells transfected with the canine beta1 subunit become adhesive, and those homotypic interactions amongst beta1 subunits of the Na(+),K(+)-ATPase occur between neighboring epithelial cells. Ouabain, a cardiotonic steroid, binds to the alpha subunit of the Na(+),K(+)-ATPase, inhibits the pump activity and induces ...


Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige Apr 2019

Exercise Rescues Gene Pathways Involved In Vascular Expansion And Promotes Functional Angiogenesis In Subcutaneous White Adipose Tissue, So Yun Min, Heather Learnard, Shashi Kant, Olga Gaelikman, Raziel Rojas-Rodriguez, Tiffany Desouza, Anand Desai, John F. Keaney Jr., Silvia Corvera, Siobhan M. Craige

Open Access Articles

Exercise mitigates chronic diseases such as diabetes, cardiovascular diseases, and obesity; however, the molecular mechanisms governing protection from these diseases are not completely understood. Here we demonstrate that exercise rescues metabolically compromised high fat diet (HFD) fed mice, and reprograms subcutaneous white adipose tissue (scWAT). Using transcriptomic profiling, scWAT was analyzed for HFD gene expression changes that were rescued by exercise. Gene networks involved in vascularization were identified as prominent targets of exercise, which led us to investigate the vasculature architecture and endothelial phenotype. Vascular density in scWAT was found to be compromised in HFD, and exercise rescued this defect ...


Rac1 Activity Is Modulated By Huntingtin And Dysregulated In Models Of Huntington's Disease, Adelaide Tousley, Anastasia Khvorova, Neil Aronin, Kimberly B. Kegel-Gleason Feb 2019

Rac1 Activity Is Modulated By Huntingtin And Dysregulated In Models Of Huntington's Disease, Adelaide Tousley, Anastasia Khvorova, Neil Aronin, Kimberly B. Kegel-Gleason

RNA Therapeutics Institute Publications

BACKGROUND: Previous studies suggest that Huntingtin, the protein mutated in Huntington's disease (HD), is required for actin based changes in cell morphology, and undergoes stimulus induced targeting to plasma membranes where it interacts with phospholipids involved in cell signaling. The small GTPase Rac1 is a downstream target of growth factor stimulation and PI 3-kinase activity and is critical for actin dependent membrane remodeling.

OBJECTIVE: To determine if Rac1 activity is impaired in HD or regulated by normal Huntingtin.

METHODS: Analyses were performed in differentiated control and HD human stem cells and HD Q140/Q140 knock-in mice. Biochemical methods included ...


A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout Jan 2019

A Persistence Detector For Metabolic Network Rewiring In An Animal, Jote T. Bulcha, Gabrielle E. Giese, Zulfikar Ali, Yong-Uk Lee, Melissa D. Walker, Amy D. Holdorf, L. Safak Yilmaz, Robert C. Brewster, Albertha J. M. Walhout

Open Access Articles

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental inputs. Caenorhabditis elegans has two breakdown pathways for the short-chain fatty acid propionate: a canonical, vitamin B12-dependent pathway and a propionate shunt that is used when vitamin B12 levels are low. The shunt pathway is kept off when there is sufficient flux through the canonical pathway, likely to avoid generating shunt-specific toxic intermediates. Here, we discovered a transcriptional regulatory circuit that activates shunt gene expression upon propionate buildup. Nuclear hormone receptor 10 (NHR-10) and NHR-68 function together as a "persistence detector" in a type 1, coherent feed-forward loop ...


Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti Dec 2018

Orbit: A New Paradigm For Genetic Engineering Of Mycobacterial Chromosomes, Kenan C. Murphy, Samantha J. Nelson, Subhalaxmi Nambi, Kadamba Papavinasasundaram, Christina E. Baer, Christopher M. Sassetti

Open Access Articles

Two efficient recombination systems were combined to produce a versatile method for chromosomal engineering that obviates the need to prepare double-stranded DNA (dsDNA) recombination substrates. A synthetic "targeting oligonucleotide" is incorporated into the chromosome via homologous recombination mediated by the phage Che9c RecT annealase. This oligonucleotide contains a site-specific recombination site for the directional Bxb1 integrase (Int), which allows the simultaneous integration of a "payload plasmid" that contains a cognate recombination site and a selectable marker. The targeting oligonucleotide and payload plasmid are cotransformed into a RecT- and Int-expressing strain, and drug-resistant homologous recombinants are selected in a single step ...


The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski Dec 2018

The Caenorhabditis Elegans Oxidative Stress Response Requires The Nhr-49 Transcription Factor, Queenie Hu, Dayana R. D'Amora, Lesley T. Macneil, Albertha J. M. Walhout, Terrance J. Kubiseski

Open Access Articles

The overproduction of reactive oxygen species (ROS) in cells can lead to the development of diseases associated with aging. We have previously shown that C. elegans BRAP-2 (Brca1 associated binding protein 2) regulates phase II detoxification genes such as gst-4, by increasing SKN-1 activity. Previously, a transcription factor (TF) RNAi screen was conducted to identify potential activators that are required to induce gst-4 expression in brap-2(ok1492) mutants. The lipid metabolism regulator NHR-49/HNF4 was among 18 TFs identified. Here, we show that knockdown of nhr-49 suppresses the activation of gst-4 caused by brap-2 inactivation and that gain-of-function alleles of ...


Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer Dec 2018

Potent Cas9 Inhibition In Bacterial And Human Cells By Acriic4 And Acriic5 Anti-Crispr Proteins, Jooyoung Lee, Aamir Mir, Alireza Edraki, Bianca Garcia, Nadia Amrani, Hannah E. Lou, Ildar Gainetdinov, April Pawluk, Raed Ibraheim, Xin D. Gao, Pengpeng Liu, Alan R. Davidson, Karen L. Maxwell, Erik J. Sontheimer

Open Access Articles

In their natural settings, CRISPR-Cas systems play crucial roles in bacterial and archaeal adaptive immunity to protect against phages and other mobile genetic elements, and they are also widely used as genome engineering technologies. Previously we discovered bacteriophage-encoded Cas9-specific anti-CRISPR (Acr) proteins that serve as countermeasures against host bacterial immunity by inactivating their CRISPR-Cas systems (A. Pawluk, N. Amrani, Y. Zhang, B. Garcia, et al., Cell 167:1829-1838.e9, 2016, https://doi.org/10.1016/j.cell.2016.11.017). We hypothesized that the evolutionary advantages conferred by anti-CRISPRs would drive the widespread occurrence of these proteins in nature (K ...


Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker Nov 2018

Stress-Responsive And Metabolic Gene Regulation Are Altered In Low S-Adenosylmethionine, Wei Ding, Daniel P. Higgins, Dilip K. Yadav, Adwait A. Godbole, Read Pukkila-Worley, Amy K. Walker

Open Access Articles

S-adenosylmethionine (SAM) is a donor which provides the methyl groups for histone or nucleic acid modification and phosphatidylcholine production. SAM is hypothesized to link metabolism and chromatin modification, however, its role in acute gene regulation is poorly understood. We recently found that Caenorhabditis elegans with reduced SAM had deficiencies in H3K4 trimethylation (H3K4me3) at pathogen-response genes, decreasing their expression and limiting pathogen resistance. We hypothesized that SAM may be generally required for stress-responsive transcription. Here, using genetic assays, we show that transcriptional responses to bacterial or xenotoxic stress fail in C. elegans with low SAM, but that expression of heat ...


Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong Nov 2018

Genome-Wide Crispr Screens For Shiga Toxins And Ricin Reveal Golgi Proteins Critical For Glycosylation, Songhai Tian, Khaja Muneeruddin, Mei Yuk Choi, Liang Tao, Robiul H. Bhuiyan, Yuhsuke Ohmi, Keiko Furukawa, Koichi Furukawa, Sebastian Boland, Scott A. Shaffer, Rosalyn M. Adam, Min Dong

Open Access Articles

Glycosylation is a fundamental modification of proteins and membrane lipids. Toxins that utilize glycans as their receptors have served as powerful tools to identify key players in glycosylation processes. Here, we carried out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9-mediated genome-wide loss-of-function screens using two related bacterial toxins, Shiga-like toxins (Stxs) 1 and 2, which use a specific glycolipid, globotriaosylceramide (Gb3), as receptors, and the plant toxin ricin, which recognizes a broad range of glycans. The Stxs screens identified major glycosyltransferases (GTs) and transporters involved in Gb3 biosynthesis, while the ricin screen identified GTs and transporters involved in N-linked ...


A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder Aug 2018

A Population Of Gut Epithelial Enterochromaffin Cells Is Mechanosensitive And Requires Piezo2 To Convert Force Into Serotonin Release, Constanza Alcaino, Kaitlyn R. Knutson, Anthony J. Treichel, Gulcan Yildiz, Peter R. Strege, David R. Linden, Joyce H. Li, Andrew B. Leiter, Joseph H. Szurszewski, Gianrico Farrugia, Arthur Beyder

Open Access Articles

Enterochromaffin (EC) cells constitute the largest population of intestinal epithelial enteroendocrine (EE) cells. EC cells are proposed to be specialized mechanosensory cells that release serotonin in response to epithelial forces, and thereby regulate intestinal fluid secretion. However, it is unknown whether EE and EC cells are directly mechanosensitive, and if so, what the molecular mechanism of their mechanosensitivity is. Consequently, the role of EE and EC cells in gastrointestinal mechanobiology is unclear. Piezo2 mechanosensitive ion channels are important for some specialized epithelial mechanosensors, and they are expressed in mouse and human EC cells. Here, we use EC and EE cell ...


Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr. Jul 2018

Llc Tumor Cells-Derivated Factors Reduces Adipogenesis In Co-Culture System, Magno Alves Lopes, Felipe Oliveira Franco, Felipe Henriques, Sidney Barnabe Peres, Miguel Luiz Batista Jr.

Open Access Articles

Cancer cachexia (CC) is a multifactorial syndrome with an unknown etiology. The primary symptom is the progressive reduction of the body weight. Recently, down-regulation of adipogenic and lipogenic genes were demonstrated to be early affected during cachexia progression in adipose tissue (AT), resulting in AT remodeling. Thus, this study aimed to evaluate in a co-culture system the influence of the Lewis Lung Carcinoma (LLC) tumor cells (c/c-LLC) in an established pre-adipocyte cell line 3T3-L1 adipogenic capacity. c/c-LLC in the presence of 3T3-L1 caused a reduction in lipids accumulation, suggesting that secretory tumor cells products may affect adipogenesis. Interestingly ...


Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner Jul 2018

Activities And Classroom Demonstrations In Biological Physics: A Resource Document, Philip C. Nelson, William Berner

Department of Physics Papers

We give detailed recipes for a number of classroom demonstrations relevant to biological physics instruction. We developed them mainly for use in 2nd-3rd year undergraduate Physics courses. But you can (and we do) use them for primary school, through high school, up to PhD candidates. You adapt the words for each audience, but a phenomenon is a phenomenon.

We also outline a 1-hour introduction to Python for undergraduate scientific computing.

Finally we document some outcomes from courses taught at U Pennsylvania using these resources and others cited here. This material was presented at a workshop at the AAPT meeting in ...


Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu Jul 2018

Inhibition Of Protein Arginine Methyltransferase 5 Enhances Hepatic Mitochondrial Biogenesis, Lei Huang, Jehnan Liu, Xiao-Ou Zhang, Katelyn Sibley, Sonia M. Najjar, Mary M. Lee, Joae Qiong Wu

Open Access Articles

Protein arginine methyltransferase 5 (PRMT5) regulates gene expression either transcriptionallyly by symmetric dimethylation of arginine residues on histones H4R3, H3R8 and H2AR3, or at the post-translational level by methylation of non-histone target proteins. While emerging evidence suggests that PRMT5 functions as an oncogene, its role in metabolic diseases is not well defined. We investigated the role of PRMT5 in promoting high fat-induced hepatic steatosis. High fat diet up-regulated PRMT5 levels in the liver, but not in other metabolically relevant tissues such as skeletal muscle or white and brown adipose tissue. This was associated with repression of master transcription regulators involved ...


Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis Jun 2018

Role Of The Mapk/Cjun Nh2-Terminal Kinase Signaling Pathway In Starvation-Induced Autophagy, Seda Barutcu, Nomeda Girnius, Santiago Vernia, Roger J. Davis

Davis Lab Publications

Autophagy is required for cellular homeostasis and can determine cell viability in response to stress. It is established that MTOR is a master regulator of starvation-induced macroautophagy/autophagy, but recent studies have also implicated an essential role for the MAPK8/cJun NH2-terminal kinase 1 signal transduction pathway. We found that MAPK8/JNK1 and MAPK9/JNK2 were not required for autophagy caused by starvation or MTOR inhibition in murine fibroblasts and epithelial cells. These data demonstrate that MAPK8/9 has no required role in starvation-induced autophagy. We conclude that the role of MAPK8/9 in autophagy may be context-dependent and more ...


Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech Jun 2018

Neuronal Modulation Of Brown Adipose Activity Through Perturbation Of White Adipocyte Lipogenesis, Adilson L. Guilherme, David J. Pedersen, Felipe Henriques, Alexander H. Bedard, Elizabeth Henchey, Mark Kelly, Donald A. Morgan, Kamal Rahmouni, Michael P. Czech

Open Access Articles

OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT).

METHODS AND RESULTS: Induced deletion of FASN in all adipocytes in mature mice (iAdFASNKO) enhanced sympathetic innervation and neuronal activity as well as UCP1 expression in both WAT and BAT. This ...


Biology Of Exosomes And Their Microrna Cargos In Human And Bovine Milk, Amy Lynn Leiferman Jun 2018

Biology Of Exosomes And Their Microrna Cargos In Human And Bovine Milk, Amy Lynn Leiferman

Public Access Theses and Dissertations from the College of Education and Human Sciences

Exosomes are small, cargo-containing vesicles secreted by cells to facilitate intercellular communication. Of exosome cargos, microRNAs are especially interesting because of their involvement in gene regulation. Recently, our lab has shown that exosomes and their microRNA cargo are absorbed through the diet and elicit effects exogenously. Human and animal milk contain exosomes, which may have implications in infant and adult nutrition. There is evidence that bovine milk exosomes enhance growth of murine C2C12 myotube cell cultures, but whether this translates to muscle in vivo is unknown. The USDA National Nutrient Database for Standard Reference is lacking up-to-date information about human ...


The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis Jun 2018

The Cjun Nh2-Terminal Kinase (Jnk) Signaling Pathway Promotes Genome Stability And Prevents Tumor Initiation, Nomeda A. Girnius, Yvonne J. K. Edwards, David S. Garlick, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Breast cancer is the most commonly diagnosed malignancy in women. Analysis of breast cancer genomic DNA indicates frequent loss-of-function mutations in components of the cJUN NH2-terminal kinase (JNK) signaling pathway. Since JNK signaling can promote cell proliferation by activating the AP1 transcription factor, this apparent association of reduced JNK signaling with tumor development was unexpected. We examined the effect of JNK deficiency in the murine breast epithelium. Loss of JNK signaling caused genomic instability and the development of breast cancer. Moreover, JNK deficiency caused widespread early neoplasia and rapid tumor formation in a murine model of breast cancer. This tumor ...


Transcriptional Correlates Of Proximal-Distal Identify And Regeneration Timing In Axolotl Limbs, S. Randal Voss, David Murrugarra, Tyler B. Jensen, James R Monaghan Jun 2018

Transcriptional Correlates Of Proximal-Distal Identify And Regeneration Timing In Axolotl Limbs, S. Randal Voss, David Murrugarra, Tyler B. Jensen, James R Monaghan

Neuroscience Faculty Publications

Cells within salamander limbs retain memories that inform the correct replacement of amputated tissues at different positions along the length of the arm, with proximal and distal amputations completing regeneration at similar times. We investigated the possibility that positional memory is associated with variation in transcript abundances along the proximal-distal limb axis. Transcripts were deeply sampled from Ambystoma mexicanum limbs at the time they were administered fore arm vs upper arm amputations, and at 19 post-amputation time points. After amputation and prior to regenerative outgrowth, genes typically expressed by differentiated muscle cells declined more rapidly in upper arms while cell ...


Rna Polymerase Ii Transcription Attenuation At The Yeast Dna Repair Gene, Def1, Involves Sen1-Dependent And Polyadenylation Site-Dependent Termination, Courtney Whalen, Christine Tuohy, Thomas Tallo, James W. Kaufman, Claire Moore, Jason N. Kuehner May 2018

Rna Polymerase Ii Transcription Attenuation At The Yeast Dna Repair Gene, Def1, Involves Sen1-Dependent And Polyadenylation Site-Dependent Termination, Courtney Whalen, Christine Tuohy, Thomas Tallo, James W. Kaufman, Claire Moore, Jason N. Kuehner

Open Access Articles

Termination of RNA Polymerase II (Pol II) activity serves a vital cellular role by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast Saccharomyces cerevisiae, Pol II termination is carried out by cleavage and polyadenylation factor (CPF-CF) and Nrd1-Nab3-Sen1 (NNS) complexes, which operate primarily at mRNA and non-coding RNA genes, respectively. Premature Pol II termination (attenuation) contributes to gene regulation, but there is limited knowledge of its prevalence and biological significance. In particular, it is unclear how much crosstalk occurs between CPF-CF and NNS complexes and how Pol II attenuation is modulated during stress adaptation. In ...


Regulation Of Juvenile Hormone Synthesis By 20-Hydroxyecdysone In The Yellow-Fever Mosquito, Aedes Aegypti, Maria Areiza May 2018

Regulation Of Juvenile Hormone Synthesis By 20-Hydroxyecdysone In The Yellow-Fever Mosquito, Aedes Aegypti, Maria Areiza

FIU Electronic Theses and Dissertations

In Aedes aegypti, development and reproduction are regulated by juvenile hormone III (JH). This master regulatory hormone is synthesized by the corpora allata (CA), a pair of endocrine glands with neural connections to the brain. JH titers are largely determined by the rate of biosynthetic activity of the CA and are regulated by inhibitory and stimulatory factors. Like JH, the ecdysteroid 20-hydroxyecdysone (20E) is a key hormonal regulator and has been proposed as an allatoregulator in other insects. However, its part in the regulation of JH biosynthesis of mosquitoes was unknown. The specific aims of this dissertation were to (1 ...


A Microtubule-Dynein Tethering Complex Regulates The Axonemal Inner Dynein F (I1), Tomohiro Kubo, Yuqing Hou, Deborah A. Cochran, George B. Witman, Toshiyuki Oda May 2018

A Microtubule-Dynein Tethering Complex Regulates The Axonemal Inner Dynein F (I1), Tomohiro Kubo, Yuqing Hou, Deborah A. Cochran, George B. Witman, Toshiyuki Oda

Radiology Publications and Presentations

Motility of cilia/flagella is generated by a coordinated activity of thousands of dyneins. Inner dynein arms (IDAs) are particularly important for the formation of ciliary/flagellar waveforms, but the molecular mechanism of IDA regulation is poorly understood. Here, we show using cryo-electron tomography and biochemical analyses of Chlamydomonas flagella that a conserved protein FAP44 forms a complex that tethers IDA f (I1 dynein) head domains to the A-tubule of the axonemal outer doublet microtubule. In wild-type flagella, IDA f showed little nucleotide-dependent movement except for a tilt in the fbeta head perpendicular to the microtubule-sliding direction. In the absence ...


Reconstitution Of Gabaergic Postsynapses In Host Cells, Karthik Kanamalla Apr 2018

Reconstitution Of Gabaergic Postsynapses In Host Cells, Karthik Kanamalla

Honors Scholar Theses

Type A GABA receptors (GABAARs) can be found embedded in postsynaptic membranes or in a variety of extrasynaptic locations. Receptors with synaptic function are recruited to the postsynapse by submembranous scaffolds composed of gephyrin and collybistin (CB). This study was aimed at assessing whether the ability to interact with the scaffold differentiates synaptic from non-synaptic receptors. Using HEK293 cells as an expression system, and indirect immunofluorescence (IF), co-localization of extrasynaptic receptors α1β3δ and α4β3δ with the CB-gephyrin scaffold was assessed and compared with that of the synaptic receptor α1β3γ2. Results indicated that both extrasynaptic receptors were able to colocalize with ...


Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic Apr 2018

Jip1-Mediated Jnk Activation Negatively Regulates Synaptic Plasticity And Spatial Memory, Caroline Morel, Tessi Sherrin, Norman J. Kennedy, Kelly H. Forest, Seda Barutcu, Michael Robles, Ezekiel Carpenter-Hyland, Naghum Alfulaij, Claire L. Standen, Robert A. Nichols, Morris Benveniste, Roger J. Davis, Cedomir Todorovic

University of Massachusetts Medical School Faculty Publications

The c-Jun N-terminal kinase (JNK) signal transduction pathway is implicated in learning and memory. Here, we examined the role of JNK activation mediated by the JIP1 scaffold protein. We compared male wild-type mice with a mouse model harboring a point mutation in the Jip1 gene that selectively blocks JIP1-mediated JNK activation. These male mutant mice exhibited increased NMDA receptor currents, increased NMDA receptor-mediated gene expression, and a lower threshold for induction of hippocampal long-term potentiation. The JIP1 mutant mice also displayed improved hippocampus-dependent spatial memory and enhanced associative fear conditioning. These results were confirmed using a second JIP1 mutant mouse ...


N-Terminal Sumoylation Of Centromeric Histone H3 Variant Cse4 Regulates Its Proteolysis To Prevent Mislocalization To Non-Centromeric Chromatin, Kentaro Ohkuni, Reuben Levy-Myers, Jack Warren, Wei-Chun Au, Yoshimitsu Takahashi, Richard E. Baker, Munira A. Basrai Mar 2018

N-Terminal Sumoylation Of Centromeric Histone H3 Variant Cse4 Regulates Its Proteolysis To Prevent Mislocalization To Non-Centromeric Chromatin, Kentaro Ohkuni, Reuben Levy-Myers, Jack Warren, Wei-Chun Au, Yoshimitsu Takahashi, Richard E. Baker, Munira A. Basrai

Open Access Articles

Stringent regulation of cellular levels of evolutionarily conserved centromeric histone H3 variant (CENP-A in humans, CID in flies, Cse4 in yeast) prevents its mislocalization to non-centromeric chromatin. Overexpression and mislocalization of CENP-A has been observed in cancers and leads to aneuploidy in yeast, flies, and human cells. Ubiquitin-mediated proteolysis of Cse4 by E3 ligases such as Psh1 and Sumo-Targeted Ubiquitin Ligase (STUbL) Slx5 prevent mislocalization of Cse4. Previously, we identified Siz1 and Siz2 as the major E3 ligases for sumoylation of Cse4. In this study, we have identified lysine 65 (K65) in Cse4 as a site that regulates sumoylation and ...


Increased Liver Tumor Formation In Neutral Sphingomyelinase-2-Deficient Mice, Liansheng Zhong, Ji Na Kong, Michael B. Dinkins, Silvia Leanhart, Zhihui Zhu, Stefka D. Spassieva, Haiyan Qin, Hsuan-Pei Lin, Ahmed Elsherbini, Rebecca Wang, Xue Jiang, Mariana N. Nikolova‑Karakashian, Guanghu Wang, Erhard Bieberich Mar 2018

Increased Liver Tumor Formation In Neutral Sphingomyelinase-2-Deficient Mice, Liansheng Zhong, Ji Na Kong, Michael B. Dinkins, Silvia Leanhart, Zhihui Zhu, Stefka D. Spassieva, Haiyan Qin, Hsuan-Pei Lin, Ahmed Elsherbini, Rebecca Wang, Xue Jiang, Mariana N. Nikolova‑Karakashian, Guanghu Wang, Erhard Bieberich

Physiology Faculty Publications

Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver ...


Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst Mar 2018

Multiple Molecular Mechanisms Rescue Mtdna Disease In C. Elegans, Suraiya Haroon, Annie Li, Jaye L. Weinert, Clark Fritsch, Nolan G. Ericson, Jasmine Alexander-Floyd, Bart P. Braeckman, Cole M. Haynes, Jason H. Bielas, Tali Gidalevitz, Marc Vermulst

University of Massachusetts Medical School Faculty Publications

Genetic instability of the mitochondrial genome (mtDNA) plays an important role in human aging and disease. Thus far, it has proven difficult to develop successful treatment strategies for diseases that are caused by mtDNA instability. To address this issue, we developed a model of mtDNA disease in the nematode C. elegans, an animal model that can rapidly be screened for genes and biological pathways that reduce mitochondrial pathology. These worms recapitulate all the major hallmarks of mtDNA disease in humans, including increased mtDNA instability, loss of respiration, reduced neuromuscular function, and a shortened lifespan. We found that these phenotypes could ...


Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang Mar 2018

Cbx4 Sumoylates Prdm16 To Regulate Adipose Tissue Thermogenesis, Qingbo Chen, Lei Huang, Dongning Pan, Lihua (Julie) Zhu, Yong-Xu Wang

Open Access Articles

Transcriptional co-activator Prdm16 controls brown fat development and white fat browning, but how this thermogenic function is modulated post-translationally is poorly understood. Here, we report that Cbx4, a Polycomb group protein, is a SUMO E3 ligase for Prdm16 and that Cbx4-mediated sumoylation of Prdm16 is required for thermogenic gene expression. Cbx4 expression is enriched in brown fat and is induced in adipose tissue by acute cold exposure. Sumoylation of Prdm16 at lysine 917 by Cbx4 blocks its ubiquitination-mediated degradation, thereby augmenting its stability and thermogenic function. Moreover, this sumoylation event primes Prdm16 to be further stabilized by methyltransferase Ehmt1. Heterozygous ...


The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis Mar 2018

The Cjun Nh2-Terminal Kinase (Jnk) Pathway Contributes To Mouse Mammary Gland Remodeling During Involution, Nomeda A. Girnius, Yvonne J. K. Edwards, Roger J. Davis

University of Massachusetts Medical School Faculty Publications

Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK ...