Open Access. Powered by Scholars. Published by Universities.®

Life Sciences Commons

Open Access. Powered by Scholars. Published by Universities.®

University of Massachusetts Medical School

Cellular and Molecular Physiology

2015

Keyword
Publication
Publication Type

Articles 1 - 30 of 51

Full-Text Articles in Life Sciences

Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech Dec 2015

Endothelial Protein Kinase Map4k4 Promotes Vascular Inflammation And Atherosclerosis, Rachel J. Roth Flach, Athanasia Skoura, Anouch Matevossian, Laura V. Danai, Wei Zheng, Christian Cortes, Samit K. Bhattacharya, Myriam Aouadi, G. Nana Hagan, Joseph Yawe, Pranitha Vangala, Lorena Garcia Menendez, Marcus P. Cooper, Timothy P. Fitzgibbons, Leonard Buckbinder, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe(-/-) mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe(-/-) and Ldlr(-/-) mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic ...


Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen Dec 2015

Systematic Dissection Of Roles For Chromatin Regulators In Dynamics Of Transcriptional Response To Stress In Yeast: A Dissertation, Hsiuyi V. Chen

GSBS Dissertations and Theses

The following work demonstrates that chromatin regulators play far more pronounced roles in dynamic gene expression than they do in steady-state. Histone modifications have been associated with transcription activity. However, previous analyses of gene expression in mutants affecting histone modifications show limited alteration. I systematically dissected the effects of 83 histone mutants and 119 gene deletion mutants on gene induction/repression in response to diamide stress in yeast. Importantly, I observed far more changes in gene induction/repression than changes in steady-state gene expression. The extensive dynamic gene expression profile of histone mutants and gene deletion mutants also allowed me ...


Homozygous Knockout Of The Piezo1 Gene In The Zebrafish Is Not Associated With Anemia, Boris E. Shmukler, Nicholas C. Huston, Jonathan N. Thon, Chih-Wen Ni, George Kourkoulis, Nathan D. Lawson, Barry H. Paw, Seth L. Alper Dec 2015

Homozygous Knockout Of The Piezo1 Gene In The Zebrafish Is Not Associated With Anemia, Boris E. Shmukler, Nicholas C. Huston, Jonathan N. Thon, Chih-Wen Ni, George Kourkoulis, Nathan D. Lawson, Barry H. Paw, Seth L. Alper

Molecular, Cell and Cancer Biology Publications

We have now examined the erythroid phenotype in this zebrafish strain carrying a ZFN genomic knockout of piezo1. Genotyping was performed as previously described. In contrast to the anemic phenotype observed in zebrafish subjected to morpholino knockdown of piezo, the genomic ZFN knockout of piezo1 did not segregate either with anemia in the 3-dpf embryo or with dysmorphic erythrocyte morphology in the adult fish.


Direct Visualization Of Hiv-1 Replication Intermediates Shows That Capsid And Cpsf6 Modulate Hiv-1 Intra-Nuclear Invasion And Integration, Christopher R. Chin, Jill Perreira, George Savidis, Jocelyn M. Portmann, Aaron M. Aker, Eric M. Feeley, Miles C. Smith, Abraham L. Brass Nov 2015

Direct Visualization Of Hiv-1 Replication Intermediates Shows That Capsid And Cpsf6 Modulate Hiv-1 Intra-Nuclear Invasion And Integration, Christopher R. Chin, Jill Perreira, George Savidis, Jocelyn M. Portmann, Aaron M. Aker, Eric M. Feeley, Miles C. Smith, Abraham L. Brass

Microbiology and Physiological Systems Publications and Presentations

Direct visualization of HIV-1 replication would improve our understanding of the viral life cycle. We adapted established technology and reagents to develop an imaging approach, ViewHIV, which allows evaluation of early HIV-1 replication intermediates, from reverse transcription to integration. These methods permit the simultaneous evaluation of both the capsid protein (CA) and viral DNA genome (vDNA) components of HIV-1 in both the cytosol and nuclei of single cells. ViewHIV is relatively rapid, uses readily available reagents in combination with standard confocal microscopy, and can be done with virtually any HIV-1 strain and permissive cell lines or primary cells. Using ViewHIV ...


Membrane-Bound And Soluble Fas Ligands Have Opposite Functions In Photoreceptor Cell Death Following Separation From The Retinal Pigment Epithelium, H. Matsumoto, Y. Murakami, K. Kataoka, S. Notomi, D. Mantopoulos, G. Trichonas, J. W. Miller, M. S. Gregory, B R. Ksander, Ann Marshak-Rothstein, D. G. Vavvas Nov 2015

Membrane-Bound And Soluble Fas Ligands Have Opposite Functions In Photoreceptor Cell Death Following Separation From The Retinal Pigment Epithelium, H. Matsumoto, Y. Murakami, K. Kataoka, S. Notomi, D. Mantopoulos, G. Trichonas, J. W. Miller, M. S. Gregory, B R. Ksander, Ann Marshak-Rothstein, D. G. Vavvas

Open Access Articles

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL-/-), and mFasL-only knock-in (DeltaCS) mice. Retinal detachment in FasL-/- mice resulted in a significant reduction of photoreceptor cell death. In contrast, DeltaCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss ...


Current Questions And Possible Controversies In Autophagy, L M. Lindqvist, A K. Simon, Eric H. Baehrecke Nov 2015

Current Questions And Possible Controversies In Autophagy, L M. Lindqvist, A K. Simon, Eric H. Baehrecke

Open Access Articles

Interest in autophagy has exploded over the last decade, with publications highlighting crosstalk with several other cellular processes including secretion, endocytosis, and cell suicide pathways including apoptosis. Autophagy proteins have also been implicated in other cellular processes independently of their roles in autophagy, creating complexities in the interpretation of autophagy (Atg) mutant gene data. Interestingly, this self-eating process is a survival mechanism that can also promote cell death, but when and how autophagy may 'switch' its function is still under debate. Indeed, there are currently many models of how autophagy actually influences cell death. In this review, we highlight some ...


Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu Oct 2015

Roles Of Protein Arginine Methyltransferase 7 And Jumonji Domain-Containing Protein 6 In Adipocyte Differentiation: A Dissertation, Yu-Jie Hu

GSBS Dissertations and Theses

Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The ...


Utilizing Small Nutrient Compounds As Enhancers Of Exercise-Induced Mitochondrial Biogenesis, Daniel M. Craig, Stephen P. Ashcroft, Micah Y. Belew, Ben Stocks, Kevin Currell, Keith Baar, Andrew Philp Oct 2015

Utilizing Small Nutrient Compounds As Enhancers Of Exercise-Induced Mitochondrial Biogenesis, Daniel M. Craig, Stephen P. Ashcroft, Micah Y. Belew, Ben Stocks, Kevin Currell, Keith Baar, Andrew Philp

Open Access Articles

Endurance exercise, when performed regularly as part of a training program, leads to increases in whole-body and skeletal muscle-specific oxidative capacity. At the cellular level, this adaptive response is manifested by an increased number of oxidative fibers (Type I and IIA myosin heavy chain), an increase in capillarity and an increase in mitochondrial biogenesis. The increase in mitochondrial biogenesis (increased volume and functional capacity) is fundamentally important as it leads to greater rates of oxidative phosphorylation and an improved capacity to utilize fatty acids during sub-maximal exercise. Given the importance of mitochondrial biogenesis for skeletal muscle performance, considerable attention has ...


Age-Related Changes In The Neuronal Architecture Of Caenorhabditis Elegans: A Dissertation, Anagha Khandekar Oct 2015

Age-Related Changes In The Neuronal Architecture Of Caenorhabditis Elegans: A Dissertation, Anagha Khandekar

GSBS Dissertations and Theses

Though symptoms such as loss of vision, decline in cognition and memory are evident during aging, the underlying processes that affect neuronal function during aging are not well understood. Unlike changes in other tissues and organs, age-related changes in the nervous system affect the overall physical, mental as well as social state of human beings. To start elucidating the molecular mechanisms underlying normal age-dependent brain decline, we have characterized structural neuronal changes occurring during Caenorhabditis elegans aging. Our analysis reveals distinct neuronal alterations that arise with age and that the types of changes and their age of onset are neuronal-type ...


Hcm1 Integrates Signals From Cdk1 And Calcineurin To Control Cell Proliferation, Heather E. Arsenault, Jagoree Roy, Claudine E. Mapa, Martha S. Cyert, Jennifer A. Benanti Oct 2015

Hcm1 Integrates Signals From Cdk1 And Calcineurin To Control Cell Proliferation, Heather E. Arsenault, Jagoree Roy, Claudine E. Mapa, Martha S. Cyert, Jennifer A. Benanti

Molecular, Cell and Cancer Biology Publications

Cyclin-dependent kinase (Cdk1) orchestrates progression through the cell cycle by coordinating the activities of cell-cycle regulators. Although phosphatases that oppose Cdk1 are likely to be necessary to establish dynamic phosphorylation, specific phosphatases that target most Cdk1 substrates have not been identified. In budding yeast, the transcription factor Hcm1 activates expression of genes that regulate chromosome segregation and is critical for maintaining genome stability. Previously we found that Hcm1 activity and degradation are stimulated by Cdk1 phosphorylation of distinct clusters of sites. Here we show that, upon exposure to environmental stress, the phosphatase calcineurin inhibits Hcm1 by specifically removing activating phosphorylations ...


Regulation Of Metabolism By Hepatic Oxphos: A Dissertation, Thomas E. Akie Oct 2015

Regulation Of Metabolism By Hepatic Oxphos: A Dissertation, Thomas E. Akie

GSBS Dissertations and Theses

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis.

To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis ...


Tcf1 Is Required For The T Follicular Helper Cell Response To Viral Infection, Tuoqi Wu, Hyunmu Shin, E. Ashley Moseman, Yun Ji, Bonnie Huang, Christelle Harly, Jyoti M. Sen, Leslie J. Berg, Luca Gattinoni, Dorian B. Mcgavern, Pamela L. Schwartzberg Sep 2015

Tcf1 Is Required For The T Follicular Helper Cell Response To Viral Infection, Tuoqi Wu, Hyunmu Shin, E. Ashley Moseman, Yun Ji, Bonnie Huang, Christelle Harly, Jyoti M. Sen, Leslie J. Berg, Luca Gattinoni, Dorian B. Mcgavern, Pamela L. Schwartzberg

Open Access Articles

T follicular helper (TFH) and T helper 1 (Th1) cells generated after viral infections are critical for the control of infection and the development of immunological memory. However, the mechanisms that govern the differentiation and maintenance of these two distinct lineages during viral infection remain unclear. We found that viral-specific TFH and Th1 cells showed reciprocal expression of the transcriptions factors TCF1 and Blimp1 early after infection, even before the differential expression of the canonical TFH marker CXCR5. Furthermore, TCF1 was intrinsically required for the TFH cell response to viral infection; in the absence of TCF1, the TFH cell response ...


Diet-Responsive Gene Networks Rewire Metabolism In The Nematode Caenorhabditis Elegans To Provide Robustness Against Vitamin B12 Deficiency: A Dissertation, Emma Watson Sep 2015

Diet-Responsive Gene Networks Rewire Metabolism In The Nematode Caenorhabditis Elegans To Provide Robustness Against Vitamin B12 Deficiency: A Dissertation, Emma Watson

GSBS Dissertations and Theses

Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans.

As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates ...


Cfap54 Is Required For Proper Ciliary Motility And Assembly Of The Central Pair Apparatus In Mice, Casey W. Mckenzie, Branch Craige, Tiffany V. Kroeger, Rozzy Finn, Todd A. Wyatt, Joseph H. Sisson, Jacqueline A. Pavlik, Lara Strittmatter, Gregory M. Hendricks, George B. Witman, Lance Lee Sep 2015

Cfap54 Is Required For Proper Ciliary Motility And Assembly Of The Central Pair Apparatus In Mice, Casey W. Mckenzie, Branch Craige, Tiffany V. Kroeger, Rozzy Finn, Todd A. Wyatt, Joseph H. Sisson, Jacqueline A. Pavlik, Lara Strittmatter, Gregory M. Hendricks, George B. Witman, Lance Lee

Cell and Developmental Biology Publications

Motile cilia and flagella play critical roles in fluid clearance and cell motility, and dysfunction commonly results in the pediatric syndrome primary ciliary dyskinesia (PCD). CFAP221, also known as PCDP1, is required for ciliary and flagellar function in mice and Chlamydomonas reinhardtii, where it localizes to the C1d projection of the central microtubule apparatus and functions in a complex that regulates flagellar motility in a calcium-dependent manner. We demonstrate that the genes encoding the mouse homologues of the other C. reinhardtii C1d complex members are primarily expressed in motile ciliated tissues, suggesting a conserved function in mammalian motile cilia. The ...


Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko Sep 2015

Exploring The Role Of Fus Mutants From Stress Granule Incorporation To Nucleopathy In Amyotrophic Lateral Sclerosis: A Dissertation, Hae Kyung Ko

GSBS Dissertations and Theses

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade.

FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than ...


Weekly Treatment Of 2-Hydroxypropyl-Beta-Cyclodextrin Improves Intracellular Cholesterol Levels In Ldl Receptor Knockout Mice, Sofie M.A. Walenbergh, Tom Houben, Tim Hendrikx, Mike L.J. Jeurissen, Patrick J. Van Gorp, Nathalie Vaes, Steven W.M. Olde Damink, Fons Verheyen, Ger H. Koek, Dieter Lutjohann, Alena Grebe, Eicke Latz, Ronit Shiri-Sverdlov Sep 2015

Weekly Treatment Of 2-Hydroxypropyl-Beta-Cyclodextrin Improves Intracellular Cholesterol Levels In Ldl Receptor Knockout Mice, Sofie M.A. Walenbergh, Tom Houben, Tim Hendrikx, Mike L.J. Jeurissen, Patrick J. Van Gorp, Nathalie Vaes, Steven W.M. Olde Damink, Fons Verheyen, Ger H. Koek, Dieter Lutjohann, Alena Grebe, Eicke Latz, Ronit Shiri-Sverdlov

Open Access Articles

Recently, the importance of lysosomes in the context of the metabolic syndrome has received increased attention. Increased lysosomal cholesterol storage and cholesterol crystallization inside macrophages have been linked to several metabolic diseases, such as atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Two-hydroxypropyl-beta-cyclodextrin (HP-B-CD) is able to redirect lysosomal cholesterol to the cytoplasm in Niemann-Pick type C1 disease, a lysosomal storage disorder. We hypothesize that HP-B-CD ameliorates liver cholesterol and intracellular cholesterol levels inside Kupffer cells (KCs). Hyperlipidemic low-density lipoprotein receptor knockout (Ldlr(-/-)) mice were given weekly, subcutaneous injections with HP-B-CD or control PBS. In contrast to control injections, hyperlipidemic mice ...


Determination Of Fatty Acid Oxidation And Lipogenesis In Mouse Primary Hepatocytes, Thomas E. Akie, Marcus P. Cooper Aug 2015

Determination Of Fatty Acid Oxidation And Lipogenesis In Mouse Primary Hepatocytes, Thomas E. Akie, Marcus P. Cooper

GSBS Student Publications

Lipid metabolism in liver is complex. In addition to importing and exporting lipid via lipoproteins, hepatocytes can oxidize lipid via fatty acid oxidation, or alternatively, synthesize new lipid via de novo lipogenesis. The net sum of these pathways is dictated by a number of factors, which in certain disease states leads to fatty liver disease. Excess hepatic lipid accumulation is associated with whole body insulin resistance and coronary heart disease. Tools to study lipid metabolism in hepatocytes are useful to understand the role of hepatic lipid metabolism in certain metabolic disorders. In the liver, hepatocytes regulate the breakdown and synthesis ...


Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky Aug 2015

Investigating The Effects Of Mutant Fus On Stress Response In Amyotrophic Lateral Sclerosis: A Thesis, Laura J. Kaushansky

GSBS Dissertations and Theses

During stress, eukaryotes regulate protein synthesis in part through formation of cytoplasmic, non-membrane-bound complexes called stress granules (SGs). SGs transiently store signaling proteins and stalled translational complexes in response to stress stimuli (e.g. oxidative insult, DNA damage, temperature shifts and ER dysfunction). The functional outcome of SGs is proper translational regulation and signaling, allowing cells to overcome stress.

The fatal motor neuron disease Amyotrophic Lateral Sclerosis (ALS) develops in an age-related manner and is marked by progressive neuronal death, with cytoplasmic protein aggregation, excitotoxicity and increased oxidative stress as major hallmarks. Fused in Sarcoma/Translocated in Liposarcoma (FUS) is ...


The Influence Of The Insulin-Like Gene Family And Diet-Drug Interactions On Caenorhabditis Elegans Physiology: A Dissertation, Ashlyn D. Ritter Aug 2015

The Influence Of The Insulin-Like Gene Family And Diet-Drug Interactions On Caenorhabditis Elegans Physiology: A Dissertation, Ashlyn D. Ritter

GSBS Dissertations and Theses

Aging can be defined as the accumulation of changes affecting the maintenance of homeostatic processes over time, leading to functional decline and increased risk for disease and death. In its simplicity, aging is the systemwide deterioration of an organism. Genetic studies have identified many potential molecular mechanisms of aging including DNA damage, telomere shortening, mitochondrial dysfunction, increased oxidative stress, uncontrolled inflammation, and hormone dysregulation (reviewed in [1]). However, in reality, aging is likely to be a combination of some (or potentially all) of these mechanisms.

Interestingly, aging and metabolism are tightly coordinated. Aging is a major contributor to metabolic decline ...


Rnasek Is A V-Atpase-Associated Factor Required For Endocytosis And The Replication Of Rhinovirus, Influenza A Virus, And Dengue Virus, Jill Perreira, Aaron Aker, George Savidis, Christopher R. Chin, William M. Mcdougall, Jocelyn M. Portmann, Paul Meraner, Miles Smith, Motiur Rahman, Richard E. Baker, Annick Gauthier, Michael Franti, Abraham L. Brass Aug 2015

Rnasek Is A V-Atpase-Associated Factor Required For Endocytosis And The Replication Of Rhinovirus, Influenza A Virus, And Dengue Virus, Jill Perreira, Aaron Aker, George Savidis, Christopher R. Chin, William M. Mcdougall, Jocelyn M. Portmann, Paul Meraner, Miles Smith, Motiur Rahman, Richard E. Baker, Annick Gauthier, Michael Franti, Abraham L. Brass

Open Access Articles

Human rhinovirus (HRV) causes upper respiratory infections and asthma exacerbations. We screened multiple orthologous RNAi reagents and identified host proteins that modulate HRV replication. Here, we show that RNASEK, a transmembrane protein, was needed for the replication of HRV, influenza A virus, and dengue virus. RNASEK localizes to the cell surface and endosomal pathway and closely associates with the vacuolar ATPase (V-ATPase) proton pump. RNASEK is required for endocytosis, and its depletion produces enlarged clathrin-coated pits (CCPs) at the cell surface. These enlarged CCPs contain endocytic cargo and are bound by the scissioning GTPase, DNM2. Loss of RNASEK alters the ...


Drc3 Connects The N-Drc To Dynein G To Regulate Flagellar Waveform, Junya Awata, Kangkang Song, Jianfeng Lin, Stephen M. King, Michael J. Sanderson, Daniela Nicastro, George B. Witman Aug 2015

Drc3 Connects The N-Drc To Dynein G To Regulate Flagellar Waveform, Junya Awata, Kangkang Song, Jianfeng Lin, Stephen M. King, Michael J. Sanderson, Daniela Nicastro, George B. Witman

Cell and Developmental Biology Publications

The nexin-dynein regulatory complex (N-DRC), which is a major hub for the control of flagellar motility, contains at least 11 different subunits. A major challenge is to determine the location and function of each of these subunits within the N-DRC. We characterized a Chlamydomonas mutant defective in the N-DRC subunit DRC3. Of the known N-DRC subunits, the drc3 mutant is missing only DRC3. Like other N-DRC mutants, the drc3 mutant has a defect in flagellar motility. However, in contrast to other mutations affecting the N-DRC, drc3 does not suppress flagellar paralysis caused by loss of radial spokes. Cryo-electron tomography revealed ...


Reduced Tubulin Polyglutamylation Suppresses Flagellar Shortness In Chlamydomonas, Tomohiro Kubo, Masafumi Hirono, Takumi Aikawa, Ritsu Kamiya, George B. Witman Aug 2015

Reduced Tubulin Polyglutamylation Suppresses Flagellar Shortness In Chlamydomonas, Tomohiro Kubo, Masafumi Hirono, Takumi Aikawa, Ritsu Kamiya, George B. Witman

Cell and Developmental Biology Publications

Ciliary length control is an incompletely understood process essential for normal ciliary function. The flagella of Chlamydomonas mutants lacking multiple axonemal dyneins are shorter than normal; previously it was shown that this shortness can be suppressed by the mutation suppressor of shortness 1 (ssh1) via an unknown mechanism. To elucidate this mechanism, we carried out genetic analysis of ssh1 and found that it is a new allele of TPG2 (hereafter tpg2-3), which encodes FAP234 functioning in tubulin polyglutamylation in the axoneme. Similar to the polyglutamylation-deficient mutants tpg1 and tpg2-1, tpg2-3 axonemal tubulin has a greatly reduced level of long polyglutamate ...


Characterization Of St14a Cells For Studying Modulation Of Voltage-Gated Calcium Channels, Mandy L. Roberts-Crowley, Ann R. Rittenhouse Jul 2015

Characterization Of St14a Cells For Studying Modulation Of Voltage-Gated Calcium Channels, Mandy L. Roberts-Crowley, Ann R. Rittenhouse

Open Access Articles

In medium spiny neurons (MSNs) of the striatum, dopamine D2 receptors (D2Rs) specifically inhibit the Cav1.3 subtype of L-type Ca2+ channels (LTCs). MSNs are heterogeneous in their expression of dopamine receptors making the study of D2R pathways difficult in primary neurons. Here, we employed the ST14A cell line, derived from embryonic striatum and characterized to have properties of MSNs, to study Cav1.3 current and its modulation by neurotransmitters. Round, undifferentiated ST14A cells exhibited little to no endogenous Ca2+ current while differentiated ST14A cells expressed endogenous Ca2+ current. Transfection with LTC subunits produced functional Cav1.3 current from round ...


P53 Protects Against Genome Instability Following Centriole Duplication Failure, Bramwell G. Lambrus, Yumi Uetake, Kevin M. Clutario, Vikas Daggubati, Michael Snyder, Greenfield Sluder, Andrew J. Holland Jul 2015

P53 Protects Against Genome Instability Following Centriole Duplication Failure, Bramwell G. Lambrus, Yumi Uetake, Kevin M. Clutario, Vikas Daggubati, Michael Snyder, Greenfield Sluder, Andrew J. Holland

Cell and Developmental Biology Publications

Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin ...


Jun Kinases In Hematopoiesis, And Vascular Development And Function: A Dissertation, Kasmir Ramo Jul 2015

Jun Kinases In Hematopoiesis, And Vascular Development And Function: A Dissertation, Kasmir Ramo

GSBS Dissertations and Theses

Arterial occlusive diseases are major causes of morbidity and mortality in industrialized countries and represent a huge economic burden. The extent of the native collateral circulation is an important determinant of blood perfusion restoration and therefore the severity of tissue damage and functional impairment that ensues following arterial occlusion. Understanding the mechanisms responsible for collateral artery development may provide avenues for therapeutic intervention. Here, we identify a critical requirement for mixed lineage kinase (MLK) – cJun-NH2-terminal kinase (JNK) signaling in vascular morphogenesis and native collateral artery development. We demonstrate that Mlk2-/-Mlk3-/- mice or mice with compound JNK-deficiency in the vascular ...


Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech Jul 2015

Inducible Deletion Of Protein Kinase Map4k4 In Obese Mice Improves Insulin Sensitivity In Liver And Adipose Tissues, Laura V. Danai, Rachel J. Roth Flach, Joseph V Virbasius, Lorena Garcia Menendez, Dae Young Jung, Jong Hun Kim, Jason K. Kim, Michael P. Czech

Program in Molecular Medicine Publications and Presentations

Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with ...


Cell Size Control In The Fission Yeast Schizosaccharomyces Pombe: A Dissertation, Daniel L. Keifenheim Jun 2015

Cell Size Control In The Fission Yeast Schizosaccharomyces Pombe: A Dissertation, Daniel L. Keifenheim

GSBS Dissertations and Theses

The coordination between cell growth and division is a highly regulated process that is intimately linked to the cell cycle. Efforts to identify an independent mechanism that measures cell size have been unsuccessful. Instead, we propose that size control is an intrinsic function of the basic cell cycle machinery.

My work shows that in the fission yeast Schizosaccharomyces pombe Cdc25 accumulates in a size dependent manner. This accumulation of Cdc25 occurs over a large range of cell sizes. Additionally, experiments with short pulses of cycloheximide have shown that Cdc25 is an inherently unstable protein that quickly returns to a size ...


Intraflagellar Transport 27 Is Essential For Hedgehog Signaling But Dispensable For Ciliogenesis During Hair Follicle Morphogenesis, Ning Yang, Li Li, Thibaut Eguether, John P. Sundberg, Gregory J. Pazour, Jiang Chen Jun 2015

Intraflagellar Transport 27 Is Essential For Hedgehog Signaling But Dispensable For Ciliogenesis During Hair Follicle Morphogenesis, Ning Yang, Li Li, Thibaut Eguether, John P. Sundberg, Gregory J. Pazour, Jiang Chen

Open Access Articles

Hair follicle morphogenesis requires precisely controlled reciprocal communications, including hedgehog (Hh) signaling. Activation of the Hh signaling pathway relies on the primary cilium. Disrupting ciliogenesis results in hair follicle morphogenesis defects due to attenuated Hh signaling; however, the loss of cilia makes it impossible to determine whether hair follicle phenotypes in these cilia mutants are caused by the loss of cilia, disruption of Hh signaling, or a combination of these events. In this study, we characterized the function of Ift27, which encodes a subunit of intraflagellar transport (IFT) complex B. Hair follicle morphogenesis of Ift27-null mice was severely impaired, reminiscent ...


Loss Of Mtor Signaling Affects Cone Function, Cone Structure And Expression Of Cone Specific Proteins Without Affecting Cone Survival, Shan Ma, Aditya Venkatesh, Fernanda Langellotto, Yun Z. Le, Michael N. Hall, Markus A. Ruegg, Claudio Punzo Jun 2015

Loss Of Mtor Signaling Affects Cone Function, Cone Structure And Expression Of Cone Specific Proteins Without Affecting Cone Survival, Shan Ma, Aditya Venkatesh, Fernanda Langellotto, Yun Z. Le, Michael N. Hall, Markus A. Ruegg, Claudio Punzo

Open Access Articles

Cones are the primary photoreceptor (PR) cells responsible for vision in humans. They are metabolically highly active requiring phosphoinositide 3-kinase (PI3K) activity for long-term survival. One of the downstream targets of PI3K is the kinase mammalian target of rapamycin (mTOR), which is a key regulator of cell metabolism and growth, integrating nutrient availability and growth factor signals. Both PI3K and mTOR are part of the insulin/mTOR signaling pathway, however if mTOR is required for long-term PR survival remains unknown. This is of particular interest since deregulation of this pathway in diabetes results in reduced PR function before the onset ...


Exosomes Derived From Alcohol-Treated Hepatocytes Horizontally Transfer Liver Specific Mirna-122 And Sensitize Monocytes To Lps, Fatemeh Momen-Heravi, Shashi Bala, Karen Kodys, Gyongyi Szabo May 2015

Exosomes Derived From Alcohol-Treated Hepatocytes Horizontally Transfer Liver Specific Mirna-122 And Sensitize Monocytes To Lps, Fatemeh Momen-Heravi, Shashi Bala, Karen Kodys, Gyongyi Szabo

Open Access Articles

Hepatocyte damage and inflammation in monocytes/macrophages are central to the pathogenesis of alcoholic hepatitis (AH). MicroRNAs (miRNAs) regulate all of these processes. MiRNA-122 is abundantly expressed in hepatocytes while monocytes/macrophages have low levels. The role of exosomes in AH and possible cross talk between hepatocyte-derived exosomes and immune cells is not explored yet. Here, we show that the number of exosomes significantly increases in the sera of healthy individuals after alcohol binge drinking and in mice after binge or chronic alcohol consumption. Exosomes isolated from sera after alcohol consumption or from in vitro ethanol-treated hepatocytes contained miRNA-122. Exosomes ...