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Articles 1 - 30 of 94
Full-Text Articles in Medicine and Health Sciences
The Janus Kinase 1 Is Critical For Pancreatic Cancer Initiation And Progression, Hridaya Shrestha, Patrick Rädler, Rayane Dennaoui, Madison Wicker, Nirakar Rajbhandari, Yunguang Sun, Amy Peck, Kerry Vistisen, Aleata Triplett, Rafic Beydoun, Esta Sterneck, Dieter Saur, Hallgeir Rui, Kay-Uwe Wagner
The Janus Kinase 1 Is Critical For Pancreatic Cancer Initiation And Progression, Hridaya Shrestha, Patrick Rädler, Rayane Dennaoui, Madison Wicker, Nirakar Rajbhandari, Yunguang Sun, Amy Peck, Kerry Vistisen, Aleata Triplett, Rafic Beydoun, Esta Sterneck, Dieter Saur, Hallgeir Rui, Kay-Uwe Wagner
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRASG12D-induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant …
Xpo1 Blockade With Kpt-330 Promotes Apoptosis In Cutaneous T-Cell Lymphoma By Activating The P53-P21 And P27 Pathways, Nitin Chakravarti, Amy Boles, Rachel Burzinski, Paola Sindaco, Colleen Isabelle, Kathleen Mcconnell, Anjali Mishra, Pierluigi Porcu
Xpo1 Blockade With Kpt-330 Promotes Apoptosis In Cutaneous T-Cell Lymphoma By Activating The P53-P21 And P27 Pathways, Nitin Chakravarti, Amy Boles, Rachel Burzinski, Paola Sindaco, Colleen Isabelle, Kathleen Mcconnell, Anjali Mishra, Pierluigi Porcu
Kimmel Cancer Center Faculty Papers
Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in …
Nf-Κb As An Inducible Regulator Of Inflammation In The Central Nervous System, Sudha Anilkumar, Elizabeth Wright-Jin
Nf-Κb As An Inducible Regulator Of Inflammation In The Central Nervous System, Sudha Anilkumar, Elizabeth Wright-Jin
Department of Medicine Faculty Papers
The NF-κB (nuclear factor K-light-chain-enhancer of activated B cells) transcription factor family is critical for modulating the immune proinflammatory response throughout the body. During the resting state, inactive NF-κB is sequestered by IκB in the cytoplasm. The proteasomal degradation of IκB activates NF-κB, mediating its translocation into the nucleus to act as a nuclear transcription factor in the upregulation of proinflammatory genes. Stimuli that initiate NF-κB activation are diverse but are canonically attributed to proinflammatory cytokines and chemokines. Downstream effects of NF-κB are cell type-specific and, in the majority of cases, result in the activation of pro-inflammatory cascades. Acting as …
Stat5 Induces Androgen Receptor (Ar) Gene Transcription In Prostate Cancer And Offers A Druggable Pathway To Target Ar Signaling, Cristina Maranto, Lavannya Sabharwal, Vindhya Udhane, Samuel P. Pitzen, Braedan Mccluskey, Songyan Qi, Christine O'Connor, Savita Devi, Scott Johnson, Kenneth Jacobsohn, Anjishnu Banerjee, Kenneth A. Iczkowski, Liang Wang, Scott M. Dehm, Marja T. Nevalainen
Stat5 Induces Androgen Receptor (Ar) Gene Transcription In Prostate Cancer And Offers A Druggable Pathway To Target Ar Signaling, Cristina Maranto, Lavannya Sabharwal, Vindhya Udhane, Samuel P. Pitzen, Braedan Mccluskey, Songyan Qi, Christine O'Connor, Savita Devi, Scott Johnson, Kenneth Jacobsohn, Anjishnu Banerjee, Kenneth A. Iczkowski, Liang Wang, Scott M. Dehm, Marja T. Nevalainen
Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers
Androgen receptor (AR) drives prostate cancer (PC) growth and progression, and targeting AR signaling is the mainstay of pharmacological therapies for PC. Resistance develops relatively fast as a result of refueled AR activity. A major gap in the field is the lack of understanding of targetable mechanisms that induce persistent AR expression in castrate-resistant PC (CRPC). This study uncovers an unexpected function of active Stat5 signaling, a known promoter of PC growth and clinical progression, as a potent inducer of AR gene transcription. Stat5 suppression inhibited AR gene transcription in preclinical PC models and reduced the levels of wild-type, mutated, …
The Therapeutic Potential Of Targeting Cardiac Rgs4., Giselle Del Calvo, Teresa Baggio Lopez, Anastasios Lymperopoulos
The Therapeutic Potential Of Targeting Cardiac Rgs4., Giselle Del Calvo, Teresa Baggio Lopez, Anastasios Lymperopoulos
HPD Articles
G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a …
Implications Of Caspase 1/ Interleukin-1 Beta (Il-1Β) Signaling And Hypoxia-Inducible Factor 1-Alpha (Hif-1Α) On Diabetic Retinopathy Pathology., Drew Garber, Shu Zhu
Implications Of Caspase 1/ Interleukin-1 Beta (Il-1Β) Signaling And Hypoxia-Inducible Factor 1-Alpha (Hif-1Α) On Diabetic Retinopathy Pathology., Drew Garber, Shu Zhu
PCOM Scholarly Papers
Diabetic retinopathy (DR) is the leading cause of adult blindness and partial vision loss in modern society for hyperglycemic patients. Accordingly, new treatment options are imperative to the overall reduction of DR prevalence and the ongoing progression of already affected candidates. There are many diseases that are the direct result of specific inflammatory processes. In this literature, DR is looked at as a potential disease that can be alleviated by targeting caspase 1/ interleukin-1 beta (IL-1β), and hypoxia-inducible factor 1-alpha (HIF-1α) signaling pathways and reducing cytokine mobilization within retinal tissues. Caspase-1 is thought to be upregulated during retinal capillary degeneration …
Scutellaria Baicalensis Enhances 5-Fluorouracil-Based Chemotherapy Via Inhibition Of Proliferative Signaling Pathways, Haizhou Liu, Hui Liu, Zhiyi Zhou, Jessica Chung, Guojing Zhang, Jin Chang, Robert A Parise, Edward Chu, John C Schmitz
Scutellaria Baicalensis Enhances 5-Fluorouracil-Based Chemotherapy Via Inhibition Of Proliferative Signaling Pathways, Haizhou Liu, Hui Liu, Zhiyi Zhou, Jessica Chung, Guojing Zhang, Jin Chang, Robert A Parise, Edward Chu, John C Schmitz
Abington Jefferson Health Papers
Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and …
Cardiac Rgs Proteins In Human Heart Failure And Atrial Fibrillation: Focus On Rgs4., Jordana I. Borges, Malka S. Suster, Anastasios Lymperopoulos
Cardiac Rgs Proteins In Human Heart Failure And Atrial Fibrillation: Focus On Rgs4., Jordana I. Borges, Malka S. Suster, Anastasios Lymperopoulos
HPD Articles
The regulator of G protein signaling (RGS) proteins are crucial for the termination of G protein signals elicited by G protein-coupled receptors (GPCRs). This superfamily of cell membrane receptors, by far the largest and most versatile in mammals, including humans, play pivotal roles in the regulation of cardiac function and homeostasis. Perturbations in both the activation and termination of their G protein-mediated signaling underlie numerous heart pathologies, including heart failure (HF) and atrial fibrillation (AFib). Therefore, RGS proteins play important roles in the pathophysiology of these two devasting cardiac diseases, and several of them could be targeted therapeutically. Although close …
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Intestinal Neuropod Cell Gucy2c Regulates Visceral Pain, Joshua R. Barton, Annie K. Londregran, Tyler D. Alexander, Ariana A. Entezari, Shely Bar-Ad, Lan Cheng, Angelo C. Lepore, Adam E. Snook, Manuel Covarrubias, Scott A. Waldman
Department of Pharmacology and Experimental Therapeutics Faculty Papers
Visceral pain (VP) is a global problem with complex etiologies and limited therapeutic options. Guanylyl cyclase C (GUCY2C), an intestinal receptor producing cyclic GMP(cGMP), which regulates luminal fluid secretion, has emerged as a therapeutic target for VP. Indeed, FDA-approved GUCY2C agonists ameliorate VP in patients with chronic constipation syndromes, although analgesic mechanisms remain obscure. Here, we revealed that intestinal GUCY2C was selectively enriched in neuropod cells, a type of enteroendocrine cell that synapses with submucosal neurons in mice and humans. GUCY2Chi neuropod cells associated with cocultured dorsal root ganglia neurons and induced hyperexcitability, reducing the rheobase and increasing the resulting …
Kras Inhibitor That Simultaneously Inhibits Nucleotide Exchange Activity And Effector Engagement, Cynthia V Pagba, Amit K Gupta, Ali K Naji, Dharini Van Der Hoeven, Kelly Churion, Xiaowen Liang, Jacob Jakubec, Magnus Hook, Yan Zuo, Marisela Martinez De Kraatz, Jeffrey A Frost, Alemayehu A Gorfe
Kras Inhibitor That Simultaneously Inhibits Nucleotide Exchange Activity And Effector Engagement, Cynthia V Pagba, Amit K Gupta, Ali K Naji, Dharini Van Der Hoeven, Kelly Churion, Xiaowen Liang, Jacob Jakubec, Magnus Hook, Yan Zuo, Marisela Martinez De Kraatz, Jeffrey A Frost, Alemayehu A Gorfe
Journal Articles
We describe a small molecule ligand ACA-14 (2-hydroxy-5-{[(2-phenylcyclopropyl) carbonyl] amino} benzoic acid) as an initial lead for the development of direct inhibitors of KRAS, a notoriously difficult anticancer drug target. We show that the compound binds to KRAS near the switch regions with affinities in the low micromolar range and exerts different effects on KRAS interactions with binding partners. Specifically, ACA-14 impedes the interaction of KRAS with its effector Raf and reduces both intrinsic and SOS-mediated nucleotide exchange rates. Likely as a result of these effects, ACA-14 inhibits signal transduction through the MAPK pathway in cells expressing mutant KRAS and …
Serpinb3 Drives Cancer Stem Cell Survival In Glioblastoma, Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen Mccortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia
Serpinb3 Drives Cancer Stem Cell Survival In Glioblastoma, Adam Lauko, Josephine Volovetz, Soumya M Turaga, Defne Bayik, Daniel J Silver, Kelly Mitchell, Erin E Mulkearns-Hubert, Dionysios C Watson, Kiran Desai, Manav Midha, Jing Hao, Kathleen Mccortney, Alicia Steffens, Ulhas Naik, Manmeet S Ahluwalia, Shideng Bao, Craig Horbinski, Jennifer S Yu, Justin D Lathia
Department of Medicine Faculty Papers
Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced …
Rickettsial Pathogen Perturbs Tick Circadian Gene To Infect The Vertebrate Host, Supreet Khanal, Vikas Taank, John F. Anderson, Hameeda Sultana, Girish Neelakanta
Rickettsial Pathogen Perturbs Tick Circadian Gene To Infect The Vertebrate Host, Supreet Khanal, Vikas Taank, John F. Anderson, Hameeda Sultana, Girish Neelakanta
Biological Sciences Faculty Publications
Ixodes scapularis is a medically important tick that transmits several microbes to humans, including rickettsial pathogen Anaplasma phagocytophilum. In nature, these ticks encounter several abiotic factors including changes in temperature, humidity, and light. Many organisms use endogenously generated circadian pathways to encounter abiotic factors. In this study, we provide evidence for the first time to show that A. phagocytophilum modulates the arthropod circadian gene for its transmission to the vertebrate host. We noted a circadian oscillation in the expression of arthropod clock, bmal1, period and timeless genes when ticks or tick cells were exposed to alternate 12 h …
Endorepellin Evokes An Angiostatic Stress Signaling Cascade In Endothelial Cells., Aastha Kapoor, Carolyn G Chen, Renato V Iozzo
Endorepellin Evokes An Angiostatic Stress Signaling Cascade In Endothelial Cells., Aastha Kapoor, Carolyn G Chen, Renato V Iozzo
Department of Pathology, Anatomy, and Cell Biology Faculty Papers
Endorepellin, the C-terminal fragment of the heparan sulfate proteoglycan perlecan, influences various signaling pathways in endothelial cells by binding to VEGFR2. In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4, and GADD45α. Specifically, endorepellin evoked transient activation of VEGFR2, which, in turn, phosphorylated PERK at Thr980 Subsequently, PERK phosphorylated eIF2α at Ser51, upregulating its downstream effector proteins ATF4 and GADD45α. RNAi-mediated knockdown of PERK or eIF2α abrogated the endorepellin-mediated up-regulation of GADD45α, the ultimate effector protein of this stress signaling cascade. To functionally validate these findings, we utilized an ex …
Bioenergetic Functions In Subpopulations Of Heart Mitochondria Are Preserved In A Non-Obese Type 2 Diabetes Rat Model (Goto-Kakizaki), Nicola Lai, C. M. Kummitha, F. Loy, R. Isola, C. L. Hoppel
Bioenergetic Functions In Subpopulations Of Heart Mitochondria Are Preserved In A Non-Obese Type 2 Diabetes Rat Model (Goto-Kakizaki), Nicola Lai, C. M. Kummitha, F. Loy, R. Isola, C. L. Hoppel
Electrical & Computer Engineering Faculty Publications
A distinct bioenergetic impairment of heart mitochondrial subpopulations in diabetic cardiomyopathy is associated with obesity; however, many type 2 diabetic (T2DM) patients with high-risk for cardiovascular disease are not obese. In the absence of obesity, it is unclear whether bioenergetic function in the subpopulations of mitochondria is affected in heart with T2DM. To address this issue, a rat model of non-obese T2DM was used to study heart mitochondrial energy metabolism, measuring bioenergetics and enzyme activities of the electron transport chain (ETC). Oxidative phosphorylation in the presence of substrates for ETC and ETC activities in both populations of heart mitochondria in …
Alterations In Phosphorylation Of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection., Elizabeth K K Glennon, Laura S Austin, Nadia Arang, Heather S Kain, Fred D Mast, Kamalakannan Vijayan, John D Aitchison, Stefan H I Kappe, Alexis Kaushansky
Alterations In Phosphorylation Of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection., Elizabeth K K Glennon, Laura S Austin, Nadia Arang, Heather S Kain, Fred D Mast, Kamalakannan Vijayan, John D Aitchison, Stefan H I Kappe, Alexis Kaushansky
Articles, Abstracts, and Reports
Plasmodium parasites are highly selective when infecting hepatocytes and induce many changes within the host cell upon infection. While several host cell factors have been identified that are important for liver infection, our understanding of what facilitates the maintenance of infection remains incomplete. Here, we describe a role for phosphorylated ribosomal protein S6 (Ser235/236) (p-RPS6) in Plasmodium yoelii-infected hepatocytes. Blocking RPS6 phosphorylation prior to infection decreases the number of liver stage parasites within 24 h. Infected hepatocytes exhibit elevated levels of p-RPS6 while simultaneously abrogating the induction of phosphorylation of RPS6 in response to insulin stimulation. This is in contrast …
Targeting The Stat5 Pathway In Ph+ Acute Lymphoblastic Leukemia, Valentina Minieri, Marco De Dominici, Marja T. Nevalainen, Bruno Calabretta
Targeting The Stat5 Pathway In Ph+ Acute Lymphoblastic Leukemia, Valentina Minieri, Marco De Dominici, Marja T. Nevalainen, Bruno Calabretta
Department of Cancer Biology Faculty Papers
No abstract provided.
Extracellular Interactions Between Fibulins And Transforming Growth Factor (Tgf)-Β In Physiological And Pathological Conditions., Takeshi Tsuda
Extracellular Interactions Between Fibulins And Transforming Growth Factor (Tgf)-Β In Physiological And Pathological Conditions., Takeshi Tsuda
Department of Pediatrics Faculty Papers
Transforming growth factor (TGF)-β is a multifunctional peptide growth factor that has a vital role in the regulation of cell growth, differentiation, inflammation, and repair in a variety of tissues, and its dysregulation mediates a number of pathological conditions including fibrotic disorders, chronic inflammation, cardiovascular diseases, and cancer progression. Regulation of TGF-β signaling is multifold, but one critical site of regulation is via interaction with certain extracellular matrix (ECM) microenvironments, as TGF-β is primarily secreted as a biologically inactive form sequestrated into ECM. Several ECM proteins are known to modulate TGF-β signaling via cell⁻matrix interactions, including thrombospondins, SPARC (Secreted Protein …
Snf1 Cooperates With The Cwi Mapk Pathway To Mediate The Degradation Of Med13 Following Oxidative Stress, Stephen D Willis, David C Stieg, Kai Li Ong, Ravina Shah, Alexandra K. Strich, Julianne H Grose, Katrina F Cooper
Snf1 Cooperates With The Cwi Mapk Pathway To Mediate The Degradation Of Med13 Following Oxidative Stress, Stephen D Willis, David C Stieg, Kai Li Ong, Ravina Shah, Alexandra K. Strich, Julianne H Grose, Katrina F Cooper
Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship
Eukaryotic cells, when faced with unfavorable environmental conditions, mount either pro-survival or pro-death programs. The conserved cyclin C-Cdk8 kinase plays 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 Saccharomyces cerevisiae, oxidative stress triggers Med13 destruction, which releases cyclin C into the cytoplasm to promote mitochondrial fission and programmed cell death. The SCFGrr1 ubiquitin ligase mediates Med13 degradation dependent on the cell wall integrity pathway, MAPK Slt2. Here we show that the AMP kinase Snf1 activates a second …
The Role Of The Leukemia Inhibitory Factor Receptor In Neuroprotective Signaling, Stephanie M. Davis, Keith R. Pennypacker
The Role Of The Leukemia Inhibitory Factor Receptor In Neuroprotective Signaling, Stephanie M. Davis, Keith R. Pennypacker
Center for Advanced Translational Stroke Science Faculty Publications
Several neurotropic cytokines relay their signaling through the leukemia inhibitory factor receptor. This 190kDa subunit couples with the 130kDa gp130 subunit to transduce intracellular signaling in neurons and oligodendrocytes that leads to expression of genes associated with neurosurvival. Moreover, activation of this receptor alters the phenotype of immune cells to an anti-inflammatory one. Although cytokines that activate the leukemia inhibitory factor receptor have been studied in the context of neurodegenerative disease, therapeutic targeting of the specific receptor subunit has been understudied in by comparison. This review examines the role of this receptor in the CNS and immune system, and its …
An Intracellular Activation Of Smoothened That Is Independent Of Hedgehog Stimulation In Drosophila, Kai Jiang, Yajuan Liu, Jie Zhang, Jianhang Jia
An Intracellular Activation Of Smoothened That Is Independent Of Hedgehog Stimulation In Drosophila, Kai Jiang, Yajuan Liu, Jie Zhang, Jianhang Jia
Markey Cancer Center Faculty Publications
Smoothened (Smo), a GPCR family protein, plays a critical role in the reception and transduction of Hedgehog (Hh) signal. Smo is phosphorylated and activated on the cell surface; however, it is unknown whether Smo can be intracellularly activated. Here, we demonstrate that inactivation of the ESCRT-III causes dramatic accumulation of Smo in the ESCRT-III/MVB compartment, and subsequent activation of Hh signaling. In contrast, inactivation of ESCRTs 0–II induces mild Smo accumulation in the ESCRT-III/MVB compartment. We provide evidence that Kurtz (Krz), the Drosophila β-arrestin2, acts in parallel with the ESCRTs 0-II pathway to sort Smo to the multivesicular bodies and …
Intrinsic And Innate Defenses Of Neurons: Détente With The Herpesviruses, Lynn Enquist, David A. Leib
Intrinsic And Innate Defenses Of Neurons: Détente With The Herpesviruses, Lynn Enquist, David A. Leib
Dartmouth Scholarship
Neuroinvasive herpesviruses have evolved to efficiently infect and establish latency in neurons. The nervous system has limited capability to regenerate, so immune responses therein are carefully regulated to be nondestructive, with dependence on atypical intrinsic and innate defenses. In this article we review studies of some of these noncanonical defense pathways and how herpesvirus gene products counter them, highlighting the contributions that primary neuronal in vitro models have made to our understanding of this field.
Negative Regulation Of Urokinase Receptor Activity By A Gpi-Specific Phospholipase C In Breast Cancer Cells., Michiel Van Veen, Elisa Matas-Rico, Koen Van De Wetering, Daniela Leyton-Puig, Katarzyna M. Kedziora, Valentina De Lorenzi, Yvette Stijf-Bultsma, Bram Van Den Broek, Kees Jalink, Nicolai Sidenius, Anastassis Perrakis, Wouter H. Moolenaar
Negative Regulation Of Urokinase Receptor Activity By A Gpi-Specific Phospholipase C In Breast Cancer Cells., Michiel Van Veen, Elisa Matas-Rico, Koen Van De Wetering, Daniela Leyton-Puig, Katarzyna M. Kedziora, Valentina De Lorenzi, Yvette Stijf-Bultsma, Bram Van Den Broek, Kees Jalink, Nicolai Sidenius, Anastassis Perrakis, Wouter H. Moolenaar
Department of Dermatology and Cutaneous Biology Faculty Papers
The urokinase receptor (uPAR) is a glycosylphosphatidylinositol (GPI)-anchored protein that promotes tissue remodeling, tumor cell adhesion, migration and invasion. uPAR mediates degradation of the extracellular matrix through protease recruitment and enhances cell adhesion, migration and signaling through vitronectin binding and interactions with integrins. Full-length uPAR is released from the cell surface, but the mechanism and significance of uPAR shedding remain obscure. Here we identify transmembrane glycerophosphodiesterase GDE3 as a GPI-specific phospholipase C that cleaves and releases uPAR with consequent loss of function, whereas its homologue GDE2 fails to attack uPAR. GDE3 overexpression depletes uPAR from distinct basolateral membrane domains in …
G Protein-Coupled Receptor Kinase-2 (Grk-2) Regulates Serotonin Metabolism Through The Monoamine Oxidase Amx-2 In Caenorhabditis Elegans., Jianjun Wang, Jiansong Luo, Dipendra K. Aryal, William C. Wetsel, Richard Nass, Jeffrey L. Benovic
G Protein-Coupled Receptor Kinase-2 (Grk-2) Regulates Serotonin Metabolism Through The Monoamine Oxidase Amx-2 In Caenorhabditis Elegans., Jianjun Wang, Jiansong Luo, Dipendra K. Aryal, William C. Wetsel, Richard Nass, Jeffrey L. Benovic
Department of Biochemistry and Molecular Biology Faculty Papers
G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans Our studies demonstrate that grk-2 loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). The egg laying defect could be rescued by the expression of wild type but not by catalytically inactive grk-2 or by the selective expression of grk-2 in …
Role Of Cytokines And Chemokines In Alcohol-Induced Tumor Promotion, Danlei Chen, Fengyun Zhang, Haifeng Ren, Jia Luo, Siying Wang
Role Of Cytokines And Chemokines In Alcohol-Induced Tumor Promotion, Danlei Chen, Fengyun Zhang, Haifeng Ren, Jia Luo, Siying Wang
Pharmacology and Nutritional Sciences Faculty Publications
Excessive chronic alcohol consumption has become a worldwide health problem. The oncogenic effect of chronic alcohol consumption is one of the leading concerns. The mechanisms of alcohol-induced tumorigenesis and tumor progression are largely unknown, although many factors have been implicated in the process. This review discusses the recent progress in this research area with concentration on alcohol-induced dysregulation of cytokines and chemokines. Based on the available evidence, we propose that alcohol promotes tumor progression by the dysregulation of the cytokine/chemokine system. In addition, we discuss specific transcription factors and signaling pathways that are involved in the action of these cytokines/chemokines …
Gene Networks Activated By Specific Patterns Of Action Potentials In Dorsal Root Ganglia Neurons, P Lee, J Cohen, Dumitru Iacobas, Sanda Iacobas, R Fields
Gene Networks Activated By Specific Patterns Of Action Potentials In Dorsal Root Ganglia Neurons, P Lee, J Cohen, Dumitru Iacobas, Sanda Iacobas, R Fields
NYMC Faculty Publications
Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons …
Signaling Through Lrg1, Rho1 And Pkc1 Governs Candida Albicans Morphogenesis In Response To Diverse Cues, Jinglin L. Xie, Nora Grahl, Trevor Sless, Michelle Leach, Sang Hu Kim, Deborah Hogan
Signaling Through Lrg1, Rho1 And Pkc1 Governs Candida Albicans Morphogenesis In Response To Diverse Cues, Jinglin L. Xie, Nora Grahl, Trevor Sless, Michelle Leach, Sang Hu Kim, Deborah Hogan
Dartmouth Scholarship
The capacity to transition between distinct morphological forms is a key virulence trait for diverse fungal pathogens. A poignant example of a leading opportunistic fungal pathogen of humans for which an environmentally responsive developmental program underpins virulence is Candida albicans. C. albicans mutants that are defective in the transition between yeast and filamentous forms typically have reduced virulence. Although many positive regulators of C. albicans filamentation have been defined, there are fewer negative regulators that have been implicated in repression of filamentation in the absence of inducing cues. To discover novel negative regulators of filamentation, we screened …
Secretion Of Rhoptry And Dense Granule Effector Proteins By Nonreplicating Toxoplasma Gondii Uracil Auxotrophs Controls The Development Of Antitumor Immunity, Barbara A. Fox, Kiah L. Sanders, Leah M. Rommereim, Rebekah B. Guevara, David J. Bzik
Secretion Of Rhoptry And Dense Granule Effector Proteins By Nonreplicating Toxoplasma Gondii Uracil Auxotrophs Controls The Development Of Antitumor Immunity, Barbara A. Fox, Kiah L. Sanders, Leah M. Rommereim, Rebekah B. Guevara, David J. Bzik
Dartmouth Scholarship
Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8 …
Vegfr2 Py949 Signalling Regulates Adherens Junction Integrity And Metastatic Spread, Xiujuan Li, Narendra Padhan, Elisabet O. Sjöström, Francis P. Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz-Jaspeado, Emma Gordon, Katie Bentley, Andrew Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V. Stan, Dietmar Vestweber, Kurt Ballmer-Hofer, Christer Betsholtz, Kristian Pietras, Leif Jansson, Lena Claesson-Welsh
Vegfr2 Py949 Signalling Regulates Adherens Junction Integrity And Metastatic Spread, Xiujuan Li, Narendra Padhan, Elisabet O. Sjöström, Francis P. Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz-Jaspeado, Emma Gordon, Katie Bentley, Andrew Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V. Stan, Dietmar Vestweber, Kurt Ballmer-Hofer, Christer Betsholtz, Kristian Pietras, Leif Jansson, Lena Claesson-Welsh
Dartmouth Scholarship
The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory …
Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib
Herpes Simplex Virus And Interferon Signaling Induce Novel Autophagic Clusters In Sensory Neurons, Sarah Katzenell, David A. Leib
Dartmouth Scholarship
Herpes simplex virus 1 (HSV-1) establishes lifelong infection in the neurons of trigeminal ganglia (TG), cycling between productive infection and latency. Neuronal antiviral responses are driven by type I interferon (IFN) and are crucial to controlling HSV-1 virulence. Autophagy also plays a role in this neuronal antiviral response, but the mechanism remains obscure. In this study, HSV-1 infection of murine TG neurons triggered unusual clusters of autophagosomes, predominantly in neurons lacking detectable HSV-1 antigen. Treatment of neurons with IFN-β induced a similar response, and cluster formation by infection or IFN treatment was dependent upon an intact IFN-signaling pathway. The autophagic …
Regulation Of Stem Cell Proliferation And Cell Fate Specification By Wingless/Wnt Signaling Gradients Enriched At Adult Intestinal Compartment Boundaries, Ai Tian, Hassina Benchabane, Zhenghan Wang, Yashi Ahmed
Regulation Of Stem Cell Proliferation And Cell Fate Specification By Wingless/Wnt Signaling Gradients Enriched At Adult Intestinal Compartment Boundaries, Ai Tian, Hassina Benchabane, Zhenghan Wang, Yashi Ahmed
Dartmouth Scholarship
Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, …