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2010

Biochemistry

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Articles 1 - 18 of 18

Full-Text Articles in Cell Biology

Novel Constitutively Active Point Mutations In The Nh2 Domain Of Cxcr2 Capture The Receptor In Different Activation States, Giljun Park Dec 2010

Novel Constitutively Active Point Mutations In The Nh2 Domain Of Cxcr2 Capture The Receptor In Different Activation States, Giljun Park

Doctoral Dissertations

Chemokines are structurally and functionally related 8-10 kDa proteins defined by four conserved cysteine residues. They consist of a superfamily of proinflammatory mediators that promote the recruitment of various kinds of leukocytes and other cell types through binding to their respective chemokine receptor, a member of the GPCR family. Abnormal control of this system results in various diseases including tumorigenesis and cancer metastasis. Deregulation can occur when constitutively active mutant (CAM) chemokine receptors are locked in the “on” position. This can lead to cellular transformation/tumorigenesis. A viral CAM receptor, ORF74, that can cause tumors in humans, also has homology ...


Production, Purification And Crystallization Of Membrane Integrated Multimeric Bax, Adelbert Mark Villoso Dec 2010

Production, Purification And Crystallization Of Membrane Integrated Multimeric Bax, Adelbert Mark Villoso

UNLV Theses, Dissertations, Professional Papers, and Capstones

Apoptosis, or programmed cell death, is a vital process intimately involved in the embryonic development and homeostatic maintenance of all multicellular organisms. The committing step to apoptosis is regulated by a key protein, Bax, and its ability to integrate and form a pore structure at the outer mitochondrial membrane.


Unfortunately, the molecular details of apoptosis remain largely unclear due to the lack of structural data of integral membrane (IM) Bax. Experimental limitations of membrane protein production have slowed the pursuit of an IM-Bax structure simply because standard protocols for producing recombinant IM-Bax are inefficient in producing adequate quantities of IM-Bax ...


Virulence Of An Emerging Respiratory Pathogen, Genus Pandoraea, In Vivo And Its Interactions With Lung Epithelial Cells, Gillian Herbert, Anne Costello, Lydia Fabunmi, Kirsten Schaffer, Kevin Kavanagh, Emma M. Caraher, Máire Callaghan, Siobhan Mcclean Nov 2010

Virulence Of An Emerging Respiratory Pathogen, Genus Pandoraea, In Vivo And Its Interactions With Lung Epithelial Cells, Gillian Herbert, Anne Costello, Lydia Fabunmi, Kirsten Schaffer, Kevin Kavanagh, Emma M. Caraher, Máire Callaghan, Siobhan Mcclean

Articles

Pandoraea species have emerged as opportunistic pathogens among cystic fibrosis (CF) and non-CF patients. Pandoraea pulmonicola is the predominant Pandoraea species among Irish CF patients. The objective of this study was to investigate the pathogenicity and potential mechanisms of virulence of Irish P. pulmonicola isolates and strains from other Pandoraea species. Three patients from whom the P. pulmonicola isolates were isolated have since died. The in vivo virulence of these and other Pandoraea strains was examined by determining the ability to kill Galleria mellonella larvae. The P. pulmonicola strains generally were the most virulent of the species tested, with three ...


Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic Oct 2010

Hippocampal C-Jun-N-Terminal Kinases Serve As Negative Regulators Of Associative Learning, Tessi Sherrin, Thomas Blank, Cathrin Hippel, Martin Rayner, Roger J. Davis, Cedomir Todorovic

Davis Lab Publications

In the adult mouse, signaling through c-Jun N-terminal kinases (JNKs) links exposure to acute stress to various physiological responses. Inflammatory cytokines, brain injury and ischemic insult, or exposure to psychological acute stressors induce activation of hippocampal JNKs. Here we report that exposure to acute stress caused activation of JNKs in the hippocampal CA1 and CA3 subfields, and impaired contextual fear conditioning. Conversely, intrahippocampal injection of JNKs inhibitors sp600125 (30 mum) or D-JNKI1 (8 mum) reduced activity of hippocampal JNKs and rescued stress-induced deficits in contextual fear. In addition, intrahippocampal administration of anisomycin (100 mug/mul), a potent JNKs activator, mimicked ...


Requirement Of Jip1-Mediated C-Jun N-Terminal Kinase Activation For Obesity-Induced Insulin Resistance, Caroline Morel, Claire L. Standen, Dae Young Jung, Susan Gray, Helena Ong, Richard A. Flavell, Jason K. Kim, Roger J. Davis Oct 2010

Requirement Of Jip1-Mediated C-Jun N-Terminal Kinase Activation For Obesity-Induced Insulin Resistance, Caroline Morel, Claire L. Standen, Dae Young Jung, Susan Gray, Helena Ong, Richard A. Flavell, Jason K. Kim, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) interacting protein 1 (JIP1) has been proposed to act as a scaffold protein that mediates JNK activation. However, recent studies have implicated JIP1 in multiple biochemical processes. Physiological roles of JIP1 that are related to the JNK scaffold function of JIP1 are therefore unclear. To test the role of JIP1 in JNK activation, we created mice with a germ line point mutation in the Jip1 gene (Thr(103) replaced with Ala) that selectively blocks JIP1-mediated JNK activation. These mutant mice exhibit a severe defect in JNK activation caused by feeding of a high-fat ...


Characterization Of Metastasis-Associated Cell Surface Glycoproteins In Prostate Cancer, Lifang Yang Oct 2010

Characterization Of Metastasis-Associated Cell Surface Glycoproteins In Prostate Cancer, Lifang Yang

Theses and Dissertations in Biomedical Sciences

Prostate cancer (PCa) is a major health problem in males in the United States. Its lethality is mostly attributed to the primary tumor metastasizing to distant sites that are highly resistant to conventional therapies. Serum Prostate Specific Antigen (PSA) is the only protein biomarker used in clinic for prediction of prostate cancer recurrence following local therapies. Nonetheless, PSA lacks the ability to predict the behavior of an individual tumor in an individual patient. Therefore, development of reliable biomarkers for detection of metastatic potential in primary tumors, as well as discovery of new therapeutic targets, is in a great need for ...


The P38 Mapk Pathway Is Essential For Skeletogenesis And Bone Homeostasis In Mice, Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger J. Davis, Laurie H. Glimcher Jul 2010

The P38 Mapk Pathway Is Essential For Skeletogenesis And Bone Homeostasis In Mice, Matthew B. Greenblatt, Jae-Hyuck Shim, Weiguo Zou, Despina Sitara, Michelle Schweitzer, Dorothy Hu, Sutada Lotinun, Yasuyo Sano, Roland Baron, Jin Mo Park, Simon Arthur, Min Xie, Michael D. Schneider, Bo Zhai, Steven Gygi, Roger J. Davis, Laurie H. Glimcher

Davis Lab Publications

Nearly every extracellular ligand that has been found to play a role in regulating bone biology acts, at least in part, through MAPK pathways. Nevertheless, much remains to be learned about the contribution of MAPKs to osteoblast biology in vivo. Here we report that the p38 MAPK pathway is required for normal skeletogenesis in mice, as mice with deletion of any of the MAPK pathway member-encoding genes MAPK kinase 3 (Mkk3), Mkk6, p38a, or p38b displayed profoundly reduced bone mass secondary to defective osteoblast differentiation. Among the MAPK kinase kinase (MAP3K) family, we identified TGF-beta-activated kinase 1 (TAK1; also known ...


Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias Jun 2010

Distinct Roles Of C-Jun N-Terminal Kinase Isoforms In Neurite Initiation And Elongation During Axonal Regeneration, Monia Barnat, Herve Enslen, Friedrich Propst, Roger J. Davis, Sylvia Soares, Fatiha Nothias

Davis Lab Publications

c-Jun N-terminal kinases (JNKs) (comprising JNK1-3 isoforms) are members of the MAPK (mitogen-activated protein kinase) family, activated in response to various stimuli including growth factors and inflammatory cytokines. Their activation is facilitated by scaffold proteins, notably JNK-interacting protein-1 (JIP1). Originally considered to be mediators of neuronal degeneration in response to stress and injury, recent studies support a role of JNKs in early stages of neurite outgrowth, including adult axonal regeneration. However, the function of individual JNK isoforms, and their potential effector molecules, remained unknown. Here, we analyzed the role of JNK signaling during axonal regeneration from adult mouse dorsal root ...


Microtubule Stabilization By Bone Morphogenetic Protein Receptor-Mediated Scaffolding Of C-Jun N-Terminal Kinase Promotes Dendrite Formation, Monika Podkowa, Xin Zhao, Chi-Wing Chow, Eleanor T. Coffey, Roger J. Davis, Liliana Attisano May 2010

Microtubule Stabilization By Bone Morphogenetic Protein Receptor-Mediated Scaffolding Of C-Jun N-Terminal Kinase Promotes Dendrite Formation, Monika Podkowa, Xin Zhao, Chi-Wing Chow, Eleanor T. Coffey, Roger J. Davis, Liliana Attisano

Davis Lab Publications

Neuronal outgrowth occurs via coordinated remodeling of the cytoskeleton involving both actin and microtubules. Microtubule stabilization drives the extending neurite, yet little is known of the molecular mechanisms whereby extracellular cues regulate microtubule dynamics. Bone morphogenetic proteins (BMPs) play an important role in neuronal differentiation and morphogenesis, and BMP7 in particular induces the formation of dendrites. Here, we show that BMP7 induces stabilization of microtubules in both a MAP2-dependent neuronal cell culture model and in dendrites of primary cortical neurons. BMP7 rapidly activates c-Jun N-terminal kinases (JNKs), known regulators of microtubule dynamics, and we show that JNKs associate with the ...


Analysis Of Apoptosis Of Memory T Cells And Dendritic Cells During The Early Stages Of Viral Infection Or Exposure To Toll-Like Receptor Agonists, Kapil Bahl, Anette Hubner, Roger J. Davis, Raymond M. Welsh May 2010

Analysis Of Apoptosis Of Memory T Cells And Dendritic Cells During The Early Stages Of Viral Infection Or Exposure To Toll-Like Receptor Agonists, Kapil Bahl, Anette Hubner, Roger J. Davis, Raymond M. Welsh

Davis Lab Publications

Profound type I interferon (IFN-I)-dependent attrition of memory CD8 and CD4 T cells occurs early during many infections. It is dramatic at 2 to 4 days following lymphocytic choriomeningitis virus (LCMV) infection of mice and can be elicited by the IFN-inducing Toll receptor agonist poly(I:C). We show that this attrition occurs in many organs, indicating that it is due to T cell loss rather than redistribution. This loss correlated with elevated intracellular staining of T cells ex vivo for activated caspases but with only low levels of ex vivo staining with annexin V, probably due to the ...


Glycopeptidome Of A Heavily N-Glycosylated Cell Surface Glycoprotein Of Dictyostelium Implicated In Cell Adhesion, Christa L. Feasley, Jennifer M. Johnson, Christopher M. West, Catherine P. Chia May 2010

Glycopeptidome Of A Heavily N-Glycosylated Cell Surface Glycoprotein Of Dictyostelium Implicated In Cell Adhesion, Christa L. Feasley, Jennifer M. Johnson, Christopher M. West, Catherine P. Chia

Faculty Publications in the Biological Sciences

Genetic analysis has implicated the cell surface glycoprotein gp130 in cell interactions of the social amoeba Dictyostelium, and information about the utilization of the 18 N-glycosylation sequons present in gp130 is needed to identify critical molecular determinants of its activity. Various glycomics strategies, including mass spectrometry of native and derivatized glycans, monosaccharide analysis, exoglycosidase digestion, and antibody binding, were applied to characterize a nonanchored version secreted from Dictyostelium. s-gp130 is modified by a predominant Man8GlcNAc4 species containing bisecting and intersecting GlcNAc residues and additional high-mannose N-glycans substituted with sulfate, methyl-phosphate, and/or core R3-fucose. Site mapping confirmed the occupancy of ...


The Ubiquitin Ligase Ube4b Is Required For Efficient Epidermal Growth Factor Receptor Degradation, Natalie Sirisaengtaksin May 2010

The Ubiquitin Ligase Ube4b Is Required For Efficient Epidermal Growth Factor Receptor Degradation, Natalie Sirisaengtaksin

UT GSBS Dissertations and Theses (Open Access)

The length of time that integral membrane proteins reside on the plasma membrane is regulated by endocytosis, a process that can inactivate these proteins by removing them from the membrane and may ultimately result in their degradation. Proteins are internalized and pass through multiple distinct intracellular compartments where targeting decisions determine their fate. Membrane proteins initially enter early endosomes, and subsequently late endosomes/multivesicular bodies (MVBs), before being degraded in the lysosome. The MVB is a subset of late endosomes characterized by the appearance of small vesicles in its luminal compartment. These vesicles contain cargo proteins sorted from the limiting ...


C-Jun Nh2-Terminal Kinase Is Required For Lineage-Specific Differentiation But Not Stem Cell Self-Renewal, Ping Xu, Roger J. Davis Mar 2010

C-Jun Nh2-Terminal Kinase Is Required For Lineage-Specific Differentiation But Not Stem Cell Self-Renewal, Ping Xu, Roger J. Davis

Davis Lab Publications

The c-Jun NH(2)-terminal kinase (JNK) is implicated in proliferation. Mice with a deficiency of either the Jnk1 or the Jnk2 genes are viable, but a compound deficiency of both Jnk1 and Jnk2 causes early embryonic lethality. Studies using conditional gene ablation and chemical genetic approaches demonstrate that the combined loss of JNK1 and JNK2 protein kinase function results in rapid senescence. To test whether this role of JNK was required for stem cell proliferation, we isolated embryonic stem (ES) cells from wild-type and JNK-deficient mice. We found that Jnk1(-/-) Jnk2(-/-) ES cells underwent self-renewal, but these cells proliferated ...


Role Of The Hypothalamic-Pituitary-Thyroid Axis In Metabolic Regulation By Jnk1, Guadalupe Sabio, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Hwi Jin Ko, Helena Ong, Caroline Morel, Alfonso Mora, Judith Reilly, Jason K. Kim, Roger J. Davis Feb 2010

Role Of The Hypothalamic-Pituitary-Thyroid Axis In Metabolic Regulation By Jnk1, Guadalupe Sabio, Julie Cavanagh-Kyros, Tamera Barrett, Dae Young Jung, Hwi Jin Ko, Helena Ong, Caroline Morel, Alfonso Mora, Judith Reilly, Jason K. Kim, Roger J. Davis

Davis Lab Publications

The cJun N-terminal kinase 1 (JNK1) is implicated in diet-induced obesity. Indeed, germline ablation of the murine Jnk1 gene prevents diet-induced obesity. Here we demonstrate that selective deficiency of JNK1 in the murine nervous system is sufficient to suppress diet-induced obesity. The failure to increase body mass is mediated, in part, by increased energy expenditure that is associated with activation of the hypothalamic-pituitary-thyroid axis. Disruption of thyroid hormone function prevents the effects of nervous system JNK1 deficiency on body mass. These data demonstrate that the hypothalamic-pituitary-thyroid axis represents an important target of metabolic signaling by JNK1.


From Regulation To Pathogenesis: Employing Fluorescent Tools To Study Calcium, Janet Elaine Mccombs Jan 2010

From Regulation To Pathogenesis: Employing Fluorescent Tools To Study Calcium, Janet Elaine Mccombs

Chemistry & Biochemistry Graduate Theses & Dissertations (1986-2018)

Ca2+ is a ubiquitous and highly regulated signaling second messenger in cells, involved in a number of processes and pathways. Due to the complexity of Ca2+ signaling and its organization within a cell, it is inherently difficult to study. A number of fluorescent tools have been developed throughout the years in order to overcome these complications. Such probes allow for imaging of rapid Ca2+ transients in real-time at the single cell level, enabling the separation of the spatio-temporal aspects of Ca2+ signals. As Ca2+ is essential to cellular regulation and function, it is unsurprising Ca ...


Role Of Muscle C-Jun Nh2-Terminal Kinase 1 In Obesity-Induced Insulin Resistance, Guadalupe Sabio, Norman J. Kennedy, Julie Cavanagh-Kyros, Dae Young Jung, Hwi Jin Ko, Helena Ong, Tamera Barrett, Jason K. Kim, Roger J. Davis Jan 2010

Role Of Muscle C-Jun Nh2-Terminal Kinase 1 In Obesity-Induced Insulin Resistance, Guadalupe Sabio, Norman J. Kennedy, Julie Cavanagh-Kyros, Dae Young Jung, Hwi Jin Ko, Helena Ong, Tamera Barrett, Jason K. Kim, Roger J. Davis

Davis Lab Publications

Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH(2)-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1(-)(/)(-) mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (M(KO)) mice exhibit improved insulin sensitivity compared with control wild-type (M(WT)) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and ...


Functional Cooperation Of The Proapoptotic Bcl2 Family Proteins Bmf And Bim In Vivo, Anette Hubner, Julie Cavanagh-Kyros, Mercedes Rincon, Richard Flavell, Roger J. Davis Jan 2010

Functional Cooperation Of The Proapoptotic Bcl2 Family Proteins Bmf And Bim In Vivo, Anette Hubner, Julie Cavanagh-Kyros, Mercedes Rincon, Richard Flavell, Roger J. Davis

Davis Lab Publications

Bcl2-modifying factor (Bmf) is a member of the BH3-only group of proapoptotic proteins. To test the role of Bmf in vivo, we constructed mice with a series of mutated Bmf alleles that disrupt Bmf expression, prevent Bmf phosphorylation by the c-Jun NH(2)-terminal kinase (JNK) on Ser(74), or mimic Bmf phosphorylation on Ser(74). We report that the loss of Bmf causes defects in uterovaginal development, including an imperforate vagina and hydrometrocolpos. We also show that the phosphorylation of Bmf on Ser(74) can contribute to a moderate increase in levels of Bmf activity. Studies of compound mutants ...


Phosphorylation Of The Glycine Transporter 1, Javier Vargas Medrano Jan 2010

Phosphorylation Of The Glycine Transporter 1, Javier Vargas Medrano

Open Access Theses & Dissertations

The extracellular levels of the neurotransmitter glycine in the brain are tightly regulated by the high-affinity glycine transporter 1 (GlyT1) and the clearance of glycine depends on its rate of transport and the levels of cell surface GlyT1. Over the past years, it has been shown that PKC activation diminishes the activity and promoted phosphorylation of several neurotransmitter transporters including the dopamine, serotonin and norepinephrine transporters however, its role is unknown for the glycine transporter. To get insights into the role of PKC activation on GlyT1 regulation, we used three N-terminus GlyT1 isoforms stably expressed in porcine aortic endothelial (PAE ...