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1.
Nature ; 550(7674): 114-118, 2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28953874

RESUMEN

The ability to directly uncover the contributions of genes to a given phenotype is fundamental for biology research. However, ostensibly homogeneous cell populations exhibit large clonal variance that can confound analyses and undermine reproducibility. Here we used genome-saturated mutagenesis to create a biobank of over 100,000 individual haploid mouse embryonic stem (mES) cell lines targeting 16,970 genes with genetically barcoded, conditional and reversible mutations. This Haplobank is, to our knowledge, the largest resource of hemi/homozygous mutant mES cells to date and is available to all researchers. Reversible mutagenesis overcomes clonal variance by permitting functional annotation of the genome directly in sister cells. We use the Haplobank in reverse genetic screens to investigate the temporal resolution of essential genes in mES cells, and to identify novel genes that control sprouting angiogenesis and lineage specification of blood vessels. Furthermore, a genome-wide forward screen with Haplobank identified PLA2G16 as a host factor that is required for cytotoxicity by rhinoviruses, which cause the common cold. Therefore, clones from the Haplobank combined with the use of reversible technologies enable high-throughput, reproducible, functional annotation of the genome.


Asunto(s)
Bancos de Muestras Biológicas , Genómica/métodos , Haploidia , Células Madre Embrionarias de Ratones/metabolismo , Mutación , Animales , Vasos Sanguíneos/citología , Linaje de la Célula/genética , Resfriado Común/genética , Resfriado Común/virología , Genes Esenciales/genética , Pruebas Genéticas , Células HEK293 , Homocigoto , Humanos , Ratones , Células Madre Embrionarias de Ratones/citología , Neovascularización Fisiológica/genética , Fosfolipasas A2 Calcio-Independiente/genética , Fosfolipasas A2 Calcio-Independiente/metabolismo , Rhinovirus/patogenicidad
2.
Nature ; 468(7320): 98-102, 2010 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-20881962

RESUMEN

Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe. The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer. In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the in vivo administration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-κB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the CD49f(hi) stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.


Asunto(s)
Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Progestinas/efectos adversos , Ligando RANK/metabolismo , Animales , Apoptosis/efectos de la radiación , Diferenciación Celular , Proliferación Celular/efectos de los fármacos , Daño del ADN , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de la radiación , Femenino , Rayos gamma , Integrina alfa6/metabolismo , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/efectos adversos , Ratones , FN-kappa B/metabolismo , Osteoclastos/citología , Fosfoproteínas/análisis , Fosfoproteínas/inmunología , Progestinas/administración & dosificación , Ligando RANK/deficiencia , Ligando RANK/genética , Receptor Activador del Factor Nuclear kappa-B/deficiencia , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Transducción de Señal , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/metabolismo
3.
Proc Natl Acad Sci U S A ; 110(23): 9305-8, 2013 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-23696669

RESUMEN

Competitiveness pervades life: plants compete for sunlight and water, animals for territory and food, and humans for mates and income. Herein we investigate human competitiveness with a natural experiment and a set of behavioral experiments. We compare competitiveness in traditional fishing societies where local natural forces determine whether fishermen work in isolation or in collectives. We find sharp evidence that fishermen from individualistic societies are far more competitive than fishermen from collectivistic societies, and that this difference emerges with work experience. These findings suggest that humans can evolve traits to specific needs, support the idea that socio-ecological factors play a decisive role for individual competitiveness, and provide evidence how individualistic and collectivistic societies shape economic behavior.


Asunto(s)
Evolución Biológica , Conducta Competitiva/fisiología , Explotaciones Pesqueras/métodos , Aprendizaje/fisiología , Medio Social , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Conducta Cooperativa , Juegos Experimentales , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Estadísticas no Paramétricas
4.
Nature ; 462(7272): 505-9, 2009 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-19940926

RESUMEN

Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.


Asunto(s)
Regulación de la Temperatura Corporal/efectos de los fármacos , Regulación de la Temperatura Corporal/fisiología , Fiebre/inducido químicamente , Fiebre/metabolismo , Ligando RANK/farmacología , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Caracteres Sexuales , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Niño , Dinoprostona/metabolismo , Femenino , Fiebre/complicaciones , Perfilación de la Expresión Génica , Humanos , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Neumonía/complicaciones , Neumonía/metabolismo , Ligando RANK/administración & dosificación , Ligando RANK/antagonistas & inhibidores , Ligando RANK/metabolismo , Ratas , Ratas Wistar , Receptor Activador del Factor Nuclear kappa-B/genética , Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E
5.
J Exp Med ; 204(6): 1267-72, 2007 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-17502664

RESUMEN

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4(+)3(-) inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4(+)3(-) cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire(+) mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80(-)Aire(-) mTEC progenitors into CD80(+)Aire(+) mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire(+) mTECs and highlight a previously unrecognized role for CD4(+)3(-)RANKL(+) inducer cells in intrathymic self-tolerance.


Asunto(s)
Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Transducción de Señal/inmunología , Timo/metabolismo , Factores de Transcripción/metabolismo , Animales , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Cartilla de ADN , Células Epiteliales/citología , Células Epiteliales/metabolismo , Ratones , Ratones Transgénicos , Microscopía Confocal , Reacción en Cadena de la Polimerasa , Receptor Activador del Factor Nuclear kappa-B/inmunología , Timo/inmunología , Factores de Transcripción/inmunología , Proteína AIRE
6.
Nat Med ; 11(8): 875-9, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16007097

RESUMEN

During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world. A new coronavirus (SARS-CoV) was identified as the SARS pathogen, which triggered severe pneumonia and acute, often lethal, lung failure. Moreover, among infected individuals influenza such as the Spanish flu and the emergence of new respiratory disease viruses have caused high lethality resulting from acute lung failure. In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor. The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses.


Asunto(s)
Carboxipeptidasas/metabolismo , Enfermedades Pulmonares/enzimología , Glicoproteínas de Membrana/metabolismo , Síndrome Respiratorio Agudo Grave/enzimología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/metabolismo , Proteínas del Envoltorio Viral/metabolismo , Análisis de Varianza , Enzima Convertidora de Angiotensina 2 , Animales , Inmunohistoquímica , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/patología , Glicoproteínas de Membrana/genética , Ratones , Peptidil-Dipeptidasa A , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/genética , Síndrome Respiratorio Agudo Grave/complicaciones , Glicoproteína de la Espiga del Coronavirus , Proteínas del Envoltorio Viral/genética
7.
Laryngoscope ; 132(1): 20-25, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34106470

RESUMEN

OBJECTIVE: Despite the increase of women in surgical fields and resources toward advancing women, there is no corresponding increased representation of women in higher academic ranks and leadership. The following hypotheses are explored: 1) men and women build/maintain different relationship networks and 2) women are not similarly included within the organization and do not receive the same sponsorship as male counterparts. STUDY DESIGN: Prospective observational study. METHODS: Three months of prospective, passive organizational network data of full-time faculty at an academic medical center were collected by analysis of deidentified internal email communication logs. Data were analyzed and strength of network relationships was assessed using algorithms measuring the tie, or connection, score. Data analysis was performed with standard statistical methods and multivariable regression models, comparing network relationships based on gender and academic rank. RESULTS: Among 345 full-time faculties from surgical departments, 45.2% were female Assistant Professors, but only 9.8% were female full Professors. Men had 55% more network relationships with other men than women had with men. Gender homophily was particularly pronounced at the higher academic ranks. Men compared to women in higher ranks had 157% more network relationships to other men in lower ranks. Multivariable regression models suggested direct association of these gender differences in relationships with more women in lower academic ranks. CONCLUSION: Higher academic rank can be predicted by male gender, tenure, and number of meaningful relationships. Women are underrepresented at the leadership level in surgical departments. Gender homophily is present in collaboration networks among academic surgeons and is associated with impeded female career advancement. LEVEL OF EVIDENCE: 2 Laryngoscope, 132:20-25, 2022.


Asunto(s)
Docentes Médicos/estadística & datos numéricos , Médicos Mujeres/estadística & datos numéricos , Centros Médicos Académicos/organización & administración , Centros Médicos Académicos/estadística & datos numéricos , Femenino , Humanos , Masculino , Estudios Prospectivos , Factores Sexuales , Sexismo/prevención & control , Sexismo/estadística & datos numéricos
8.
Dev Dyn ; 239(2): 680-7, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20034073

RESUMEN

Anthrax Toxin Receptor 1 (ANTXR1; also known as Tumor Endothelial Marker 8, TEM8) is one of several genes that was recently found to be up-regulated in tumor-associated endothelial cells. In vitro, the protein can link extracellular matrix components with the actin cytoskeleton to promote cell adhesion and cell spreading. Both, ANTXR1 and the closely related ANTXR2 can bind anthrax toxin and interact with lipoprotein receptor-related protein 5 and 6, which also work as coreceptors in the WNT signaling pathway. Here, we report the cloning of chick ANTXR1 from a suppression subtractive hybridization screen for fibroblast growth factor (FGF) -inducible genes in chicken embryonic facial mesenchyme. We show that chicken ANTXR1 is dynamically expressed throughout embryogenesis, starting from Hamburger and Hamilton stage 10. Furthermore, we demonstrate that FGF signaling is sufficient, but not necessary, to induce ANTXR1 expression in chicken facial mesenchyme.


Asunto(s)
Desarrollo Embrionario , Cara/embriología , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Mesodermo/metabolismo , Receptores de Péptidos/metabolismo , Animales , Embrión de Pollo , Transducción de Señal , Proteínas Wnt/metabolismo
9.
Adv Exp Med Biol ; 658: 77-94, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-19950018

RESUMEN

The TNF family members RANKL and its receptor RANK have initially been described as factors expressed on T cells and dendritic cells (DCs), respectively, and have been shown to augment the ability of DCs to stimulate naive T cell proliferation and enhance DC survival. Since another, yet soluble receptor for RANKL, namely OPG, was initially characterized as a factor inhibiting osteoclast development and bone resorption, it was somewhat enigmatic at first why one and the same genes would be essential both for the immune system and bone development - two processes that on first sight do not have much in common. However, in a series of experiments it was conclusively shown that RANKL-expressing T cells can also activate RANK-expressing osteoclasts, and thereby in principal mimicking RANKL-expressing osteoblasts. These findings lead to a paradigm shift and helped to coin the term osteoimmunology in order to account for the crosstalk of immune cells and bone. More importantly was that these findings also provided a rationale for the bone loss observed in patients with a chronically activated immune system such as in rheumatoid arthritis, leukemias, or the like, arguing that T cells, which were activated during the course of the disease to fight it off, also express RANKL, which induces osteoclastogenesis and thereby shifts the intricate balance of bone deposition and resorption in favor of the latter. Through knockout mice it became also clear that the RANKL-RANK-OPG system is involved in other processes such as in controlling autoimmunity or immune responses in the skin. We will briefly summarize the role of RANK(L) signaling in the immune system before we discuss some of the recent data we and others have obtained on the role of RANK(L) in controlling autoimmunity and immune responses in the skin.


Asunto(s)
Sistema Inmunológico/metabolismo , Ligando RANK/metabolismo , Transducción de Señal , Animales , Resorción Ósea/inmunología , Resorción Ósea/terapia , Humanos , Terapia de Inmunosupresión , Receptor Activador del Factor Nuclear kappa-B/metabolismo
10.
Circ Res ; 101(4): e32-42, 2007 Aug 17.
Artículo en Inglés | MEDLINE | ID: mdl-17673668

RESUMEN

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.


Asunto(s)
Envejecimiento/fisiología , Presión Sanguínea/fisiología , Proteínas Portadoras/genética , Insuficiencia Cardíaca/fisiopatología , Contracción Miocárdica/fisiología , Adipoquinas , Envejecimiento/genética , Animales , Aorta , Apelina , Presión Sanguínea/genética , Proteínas Portadoras/metabolismo , Modelos Animales de Enfermedad , Conducta de Ingestión de Líquido , Ecocardiografía , Conducta Alimentaria , Femenino , Corazón/embriología , Corazón/fisiología , Insuficiencia Cardíaca/diagnóstico por imagen , Homeostasis/fisiología , Péptidos y Proteínas de Señalización Intercelular , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Miocárdica/genética , Obesidad/fisiopatología , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad
11.
Adv Exp Med Biol ; 647: 130-45, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19760071

RESUMEN

Bone-related diseases, such as osteoporosis or rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three molecules, the receptor activator of NF-kappaB(RANK), its ligand RANKL and the decoy receptor of RANKL, osteoprotegerin (OPG), attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments evolving around these molecules established their pivotal role as central regulators of osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, cancer metastases, or osteoporosis.


Asunto(s)
Enfermedades Óseas/metabolismo , Ligando RANK/fisiología , Animales , Enfermedades Óseas/terapia , Humanos
12.
Adv Exp Med Biol ; 649: 100-13, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19731623

RESUMEN

Osteoporosis or rheumatoid arthritis are bone diseases affecting hundreds of millions of people worldwide and thus pose a tremendous burden to health care. Ground-breaking discoveries made in basic science over the last decade shed light on the molecular mechanisms of bone metabolism and bone turnover. Thereby, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL and the decoy receptor of RANKL, osteoprotegerin (OPG), have been a major focus of scientists and pharmaceutical companies alike, since experiments using mice in which these genes have been inactivated unanimously established their pivotal role as central regulators ofosteoclast function. RANK(L) signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. Consequently, novel drugs specifically targeting RANK-RANKL and their signaling pathways in osteoclasts are expected to revolutionize the treatment ofvarious bone diseases, such as cancer metastases, osteoporosis, or arthropathies.


Asunto(s)
Resorción Ósea , Artropatías/metabolismo , Artropatías/patología , Osteoclastos/fisiología , Osteoprotegerina/metabolismo , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Animales , Resorción Ósea/patología , Resorción Ósea/fisiopatología , Calcineurina/metabolismo , Humanos , Artropatías/fisiopatología , Artropatías/terapia , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/fisiología , Familia-src Quinasas/metabolismo
13.
Trends Biochem Sci ; 28(5): 226-9, 2003 May.
Artículo en Inglés | MEDLINE | ID: mdl-12765832

RESUMEN

We have identified a conserved sequence segment in transmembrane receptors (including SEFs, IL17Rs) and soluble factors (including CIKS/ACT1) in eukaryotes and bacteria - the SEFIR domain. This sequence domain is part of the new STIR domain superfamily comprising also the TIR domain known to mediate TIR-TIR homotypic interactions. In TOLL/IL1R-like pathways, the cytoplasmically localized TIR domain of a receptor and the TIR domain of a soluble adaptor interact physically and activate signalling. The similarity between the SEFIR and TIR domains involves the conserved boxes 1 and 2 of the TIR domain that are implicated in homotypic dimerization, but there is no sequence similarity between SEFIR domains and the TIR sequence box 3. By analogy, we suggest that SEFIR-domain proteins function as signalling components of Toll/IL-1R-similar pathways and that their SEFIR domain mediates physical protein-protein interactions between pathway components.


Asunto(s)
Inmunidad , Proteínas/química , Proteínas/metabolismo , Receptores de Interleucina/química , Proteínas Recombinantes/química , Transducción de Señal , Secuencia de Aminoácidos , Animales , Humanos , Glicoproteínas de Membrana/metabolismo , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Proteínas/inmunología , Receptores de Superficie Celular/metabolismo , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-17 , Receptores Toll-Like
14.
Gene Expr Patterns ; 7(7): 808-16, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17602894

RESUMEN

Apoptosis signal-regulating kinase 1 (ASK1) is an important regulator of stress-induced cell death. ASK1 is activated by oxidative stress, TNF and endoplasmatic reticulum stress and activates the JNK- and p38-dependent intracellular death pathways. A number of studies have suggested that ASK1 may also have other roles in addition to its pro-apoptotic activity. Expression of ASK1 during early embryonic development has so far not been analyzed. We have identified and cloned chick ASK1 in a screen for FGF8 inducible genes in chick facial mesenchyme. Here we report the expression of chick ASK1 from the gastrulation stage (HH4) to day 4 of development, its expression in the developing inner organs and limbs, and we compare its expression to the expression of Ask1 during mouse development. Furthermore, we provide evidence that FGF signaling is required for ASK1 expression in chick nasal mesenchyme. In contrast, expression in the mouse nasal region was restricted to the epithelium and was independent of FGF signaling. Our analysis demonstrates that ASK1 has a spatially restricted and temporally dynamic expression pattern in both chick and mouse embryos, which includes conserved as well as species-specific expression domains.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , MAP Quinasa Quinasa Quinasa 5/biosíntesis , Animales , Apoptosis , Embrión de Pollo , Factores de Crecimiento de Fibroblastos/metabolismo , Riñón/embriología , Pulmón/embriología , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Noqueados , Cresta Neural/embriología , Timo/embriología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
15.
Cell Res ; 27(11): 1351-1364, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28925387

RESUMEN

Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.


Asunto(s)
Fucosiltransferasas/genética , Proteínas de Transporte de Membrana/genética , Ricina/toxicidad , Animales , Eliminación de Gen , Aparato de Golgi/metabolismo , Humanos , Ratones , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/fisiología , Mutación , Ricina/metabolismo , Sialiltransferasas/genética
17.
PLoS One ; 5(12): e14320, 2010 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-21179403

RESUMEN

The 2009 flu pandemic and the appearance of oseltamivir-resistant H1N1 influenza strains highlight the need for treatment alternatives. One such option is the creation of a protective physical barrier in the nasal cavity. In vitro tests demonstrated that iota-carrageenan is a potent inhibitor of influenza A virus infection, most importantly also of pandemic H1N1/2009 in vitro. Consequently, we tested a commercially available nasal spray containing iota-carrageenan in an influenza A mouse infection model. Treatment of mice infected with a lethal dose of influenza A PR8/34 H1N1 virus with iota-carrageenan starting up to 48 hours post infection resulted in a strong protection of mice similar to mice treated with oseltamivir. Since alternative treatment options for influenza are rare, we conclude that the nasal spray containing iota-carrageenan is an alternative to neuraminidase inhibitors and should be tested for prevention and treatment of influenza A in clinical trials in humans.


Asunto(s)
Antivirales/farmacología , Carragenina/farmacología , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Perros , Farmacorresistencia Viral , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética/métodos , Ratones , Ratones Endogámicos C57BL , Neuraminidasa/antagonistas & inhibidores , Oseltamivir/farmacología , Polímeros/química , Polisacáridos/química
18.
Science ; 325(5938): 340-3, 2009 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-19520911

RESUMEN

Innate immunity represents the first line of defense in animals. We report a genome-wide in vivo Drosophila RNA interference screen to uncover genes involved in susceptibility or resistance to intestinal infection with the bacterium Serratia marcescens. We first employed whole-organism gene suppression, followed by tissue-specific silencing in gut epithelium or hemocytes to identify several hundred genes involved in intestinal antibacterial immunity. Among the pathways identified, we showed that the JAK-STAT signaling pathway controls host defense in the gut by regulating stem cell proliferation and thus epithelial cell homeostasis. Therefore, we revealed multiple genes involved in antibacterial defense and the regulation of innate immunity.


Asunto(s)
Drosophila melanogaster/genética , Drosophila melanogaster/microbiología , Genoma de los Insectos , Inmunidad Innata/genética , Interferencia de ARN , Infecciones por Serratia/inmunología , Serratia marcescens/inmunología , Animales , Animales Modificados Genéticamente , Proliferación Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/inmunología , Células Epiteliales/citología , Células Epiteliales/fisiología , Hemocitos/inmunología , Hemocitos/metabolismo , Hemocitos/microbiología , Homeostasis , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Quinasas Janus/genética , Quinasas Janus/metabolismo , Modelos Animales , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Infecciones por Serratia/genética , Infecciones por Serratia/microbiología , Serratia marcescens/fisiología , Transducción de Señal , Células Madre/citología , Células Madre/fisiología
19.
Ann N Y Acad Sci ; 1143: 123-50, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19076348

RESUMEN

Bone-related diseases, such as osteoporosis and rheumatoid arthritis, affect hundreds of millions of people worldwide and pose a tremendous burden to health care. By deepening our understanding of the molecular mechanisms of bone metabolism and bone turnover, it became possible over the past years to devise new and promising strategies for treating such diseases. In particular, three tumor necrosis factor (TNF) family molecules, the receptor activator of NF-kappaB (RANK), its ligand RANKL, and the decoy receptor of RANKL, osteoprotegerin (OPG), have attracted the attention of scientists and pharmaceutical companies alike. Genetic experiments revolving around these molecules established their pivotal role as central regulators of osteoclast development and osteoclast function. RANK-RANKL signaling not only activates a variety of downstream signaling pathways required for osteoclast development, but crosstalk with other signaling pathways also fine-tunes bone homeostasis both in normal physiology and disease. In addition, RANKL and RANK have essential roles in lymph node formation, establishment of the thymic microenvironment, and development of a lactating mammary gland during pregnancy. Consequently, novel drugs specifically targeting RANK, RANKL, and their signaling pathways in osteoclasts are expected to revolutionize the treatment of various ailments associated with bone loss, such as arthritis, periodontal disease, cancer metastases, and osteoporosis.


Asunto(s)
Remodelación Ósea , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Linfocitos B/metabolismo , Enfermedades Óseas/metabolismo , Células Dendríticas/metabolismo , Hematopoyesis Extramedular , Humanos , Sistema de Señalización de MAP Quinasas , Osteoclastos/metabolismo , Osteoprotegerina/metabolismo , Ligando RANK/inmunología , Receptor Activador del Factor Nuclear kappa-B/inmunología
20.
Dev Dyn ; 237(7): 1893-900, 2008 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-18570253

RESUMEN

HTRA1, a member of the high temperature requirement factor A family, is a secreted serine protease that can bind to and inactivate members of the transforming growth factor-beta (TGFbeta) family, modulate insulin-like growth factor signaling and stimulate long range fibroblast growth factor (FGF) signaling in Xenopus. In vertebrates, so far homologues from mouse, human, and Xenopus have been cloned and studied. Here we report the cloning of the chicken HTRA1 homologue from a screen for FGF8 inducible genes in chick facial mesenchyme. We characterize its expression pattern from gastrulation (Hamburger and Hamilton stage 4) to day 4 of development, and in forming inner organs and limbs. We show that chick HTRA1 has a dynamic expression pattern that differs significantly from the expression of its mouse homolog. We, furthermore, demonstrate that FGF signaling is necessary and sufficient for HTRA1 expression in chick facial and forelimb mesenchyme, but is not required for HTRA1 expression in HH11 embryos.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Serina Endopeptidasas/genética , Animales , Embrión de Pollo , Factor 8 de Crecimiento de Fibroblastos/farmacología , Gastrulación/efectos de los fármacos , Gastrulación/genética , Gastrulación/fisiología , Serina Peptidasa A1 que Requiere Temperaturas Altas , Hibridación in Situ , Mesodermo/efectos de los fármacos , Mesodermo/embriología , Mesodermo/metabolismo , Ratones , Pirroles/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina Endopeptidasas/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/fisiología
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