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1.
PLoS Comput Biol ; 18(9): e1010468, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36095011

RESUMEN

Studies comparing single cell RNA-Seq (scRNA-Seq) data between conditions mainly focus on differences in the proportion of cell types or on differentially expressed genes. In many cases these differences are driven by changes in cell interactions which are challenging to infer without spatial information. To determine cell-cell interactions that differ between conditions we developed the Cell Interaction Network Inference (CINS) pipeline. CINS combines Bayesian network analysis with regression-based modeling to identify differential cell type interactions and the proteins that underlie them. We tested CINS on a disease case control and on an aging mouse dataset. In both cases CINS correctly identifies cell type interactions and the ligands involved in these interactions improving on prior methods suggested for cell interaction predictions. We performed additional mouse aging scRNA-Seq experiments which further support the interactions identified by CINS.


Asunto(s)
Perfilación de la Expresión Génica , Análisis de la Célula Individual , Animales , Teorema de Bayes , Comunicación Celular , Perfilación de la Expresión Génica/métodos , Ligandos , Ratones , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos
2.
Am J Physiol Lung Cell Mol Physiol ; 317(5): L678-L689, 2019 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-31483681

RESUMEN

Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP-5) is a member of the dual-specificity family of protein tyrosine phosphatases that negatively regulates p38 MAPK and the JNK. MKP-5-deficient mice exhibit improved muscle repair and reduced fibrosis in an animal model of muscular dystrophy. Here, we asked whether the effects of MKP-5 on muscle fibrosis extend to other tissues. Using a bleomycin-induced model of pulmonary fibrosis, we found that MKP-5-deficient mice were protected from the development of lung fibrosis, expressed reduced levels of hydroxyproline and fibrogenic genes, and displayed marked polarization towards an M1-macrophage phenotype. We showed that the profibrogenic effects of the transforming growth factor-ß1 (TGF-ß1) were inhibited in MKP-5-deficient lung fibroblasts. MKP-5-deficient fibroblasts exhibited enhanced p38 MAPK activity, impaired Smad3 phosphorylation, increased Smad7 levels, and decreased expression of fibrogenic genes. Myofibroblast differentiation was attenuated in MKP-5-deficient fibroblasts. Finally, we found that MKP-5 expression was increased in idiopathic pulmonary fibrosis (IPF)-derived lung fibroblasts but not in whole IPF lungs. These data suggest that MKP-5 plays an essential role in promoting lung fibrosis. Our results couple MKP-5 with the TGF-ß1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis.


Asunto(s)
Fosfatasas de Especificidad Dual/metabolismo , Fosfatasas de Especificidad Dual/fisiología , Fibroblastos/patología , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/metabolismo , Fibrosis Pulmonar/patología , Factor de Crecimiento Transformador beta1/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Bleomicina/toxicidad , Fosfatasas de Especificidad Dual/genética , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Sistema de Señalización de MAP Quinasas , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfatasas de la Proteína Quinasa Activada por Mitógenos/genética , Fosforilación , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Transducción de Señal
3.
Cancer Res ; 78(13): 3634-3644, 2018 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-29724718

RESUMEN

Pathogenesis and progression of lung cancer are governed by complex interactions between the environment and host genetic susceptibility, which is further modulated by genetic and epigenetic changes. Autotaxin (ATX, ENPP2) is a secreted glycoprotein that catalyzes the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like phospholipid that is further regulated by phospholipid phosphatases (PLPP). LPA's pleiotropic effects in almost all cell types are mediated through at least six G-protein coupled LPA receptors (LPAR) that exhibit overlapping specificities, widespread distribution, and differential expression profiles. Here we use both preclinical models of lung cancer and clinical samples (from patients and healthy controls) to investigate the expression levels, activity, and biological role of the above components of the ATX/LPA axis in lung cancer. ENPP2 was genetically altered in 8% of patients with lung cancer, whereas increased ATX staining and activity were detected in patient biopsies and sera, respectively. Moreover, PLPP3 expression was consistently downregulated in patients with lung cancer. Comparable observations were made in the two most widely used animal models of lung cancer, the carcinogen urethane-induced and the genetically engineered K-rasG12D -driven models, where genetic deletion of Enpp2 or Lpar1 resulted in disease attenuation, thus confirming a procarcinogenic role of LPA signaling in the lung. Expression profiling data analysis suggested that metabolic rewiring may be implicated in the procarcinogenic effects of the ATX/LPA axis in K-ras- G12D -driven lung cancer pathogenesis.Significance: These findings establish the role of ATX/LPA in lung carcinogenesis, thus expanding the mechanistic links between pulmonary fibrosis and cancer. Cancer Res; 78(13); 3634-44. ©2018 AACR.


Asunto(s)
Carcinogénesis/patología , Neoplasias Pulmonares/patología , Lisofosfolípidos/metabolismo , Fosfatidato Fosfatasa/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Anciano , Animales , Conjuntos de Datos como Asunto , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Pulmón/patología , Neoplasias Pulmonares/genética , Masculino , Ratones , Persona de Mediana Edad , Neoplasias Experimentales/inducido químicamente , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Hidrolasas Diéster Fosfóricas/genética , Receptores del Ácido Lisofosfatídico/genética , Receptores del Ácido Lisofosfatídico/metabolismo , Transducción de Señal , Uretano/toxicidad
4.
Front Med (Lausanne) ; 4: 246, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29404325

RESUMEN

Chronic lung diseases represent complex diseases with gradually increasing incidence, characterized by significant medical and financial burden for both patients and relatives. Their increasing incidence and complexity render a comprehensive, multidisciplinary, and personalized approach critically important. This approach includes the assessment of comorbid conditions including metabolic dysfunctions. Several lines of evidence show that metabolic comorbidities, including diabetes mellitus, dyslipidemia, osteoporosis, vitamin D deficiency, and thyroid dysfunction have a significant impact on symptoms, quality of life, management, economic burden, and disease mortality. Most recently, novel pathogenetic pathways and potential therapeutic targets have been identified through large-scale studies of metabolites, called metabolomics. This review article aims to summarize the current state of knowledge on the prevalence of metabolic comorbidities in chronic lung diseases, highlight their impact on disease clinical course, delineate mechanistic links, and report future perspectives on the role of metabolites as disease modifiers and therapeutic targets.

5.
Hepatology ; 65(4): 1369-1383, 2017 04.
Artículo en Inglés | MEDLINE | ID: mdl-27981605

RESUMEN

Autotaxin (ATX) is a secreted lysophospholipase D that catalyzes the production of lysophosphatidic acid (LPA), a pleiotropic growth-factor-like lysophospholipid. Increased ATX expression has been detected in various chronic inflammatory disorders and different types of cancer; however, little is known about its role and mode of action in liver fibrosis and cancer. Here, increased ATX expression was detected in chronic liver disease (CLD) patients of different etiologies, associated with shorter overall survival. In mice, different hepatotoxic stimuli linked with the development of different forms of CLDs were shown to stimulate hepatocyte ATX expression, leading to increased LPA levels, activation of hepatic stellate cells (HSCs), and amplification of profibrotic signals. Hepatocyte-specific, conditional genetic deletion and/or transgenic overexpression of ATX established a liver profibrotic role for ATX/LPA, whereas pharmacological ATX inhibition studies suggested ATX as a possible therapeutic target in CLDs. In addition, hepatocyte ATX ablation and the consequent deregulation of lipid homeostasis was also shown to attenuate hepatocellular carcinoma (HCC) development, thus implicating ATX/LPA in the causative link of cirrhosis and HCC. CONCLUSION: ATX is a novel player in the pathogenesis of liver fibrosis and cancer and a promising therapeutic target. (Hepatology 2017;65:1369-1383).


Asunto(s)
Benzoxazoles/farmacología , Carcinoma Hepatocelular/patología , Cirrosis Hepática/patología , Neoplasias Hepáticas/patología , Hidrolasas Diéster Fosfóricas/genética , Piperazinas/farmacología , Animales , Biopsia con Aguja , Carcinoma Hepatocelular/genética , Estudios de Casos y Controles , Células Cultivadas , Enfermedad Crónica , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eliminación de Gen , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Inmunohistoquímica , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , Ratones , Ratones Endogámicos C57BL , Terapia Molecular Dirigida , Hidrolasas Diéster Fosfóricas/efectos de los fármacos
6.
Dev Cell ; 17(5): 617-25, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19922867

RESUMEN

Nuclear pore complexes (NPCs) mediate all selective bidirectional transport between the nucleus and the cytoplasm. Additional functions for NPCs and their constituent proteins (nucleoporins) are emerging, some independent of classical transport. Specifically, enzymatic activities at the NPC regulate nucleocytoplasmic transport and use the NPC as a regulatory scaffold. Also, nucleoporins may regulate gene expression by contacting chromatin. Discriminating between effects on transport, scaffolding, and gene expression is a major challenge in understanding the role of the NPC in signaling and development.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Proteínas de Complejo Poro Nuclear/metabolismo , Animales , Transporte Biológico , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Humanos , Proteínas de Complejo Poro Nuclear/ultraestructura , Transducción de Señal
7.
Nat Cell Biol ; 11(7): 890-5, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19525935

RESUMEN

Epidermal injury initiates a cascade of inflammation, epithelial remodelling and integument repair at wound sites. The regeneration of the extracellular barrier and damaged tissue repair rely on the precise orchestration of epithelial responses triggered by the injury. Grainy head (Grh) transcription factors induce gene expression to crosslink the extracellular barrier in wounded flies and mice. However, the activation mechanisms and functions of Grh factors in re-epithelialization remain unknown. Here we identify stitcher (stit), a new Grh target in Drosophila melanogaster. stit encodes a Ret-family receptor tyrosine kinase required for efficient epidermal wound healing. Live imaging analysis reveals that Stit promotes actin cable assembly during wound re-epithelialization. Stit activation also induces extracellular signal-regulated kinase (ERK) phosphorylation along with the Grh-dependent expression of stit and barrier repair genes at the wound sites. The transcriptional stimulation of stit on injury triggers a positive feedback loop increasing the magnitude of epithelial responses. Thus, Stit activation upon wounding coordinates cytoskeletal rearrangements and the level of Grh-mediated transcriptional wound responses.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/enzimología , Epidermis/lesiones , Epidermis/metabolismo , Proteínas Tirosina Quinasas/fisiología , Factores de Transcripción/metabolismo , Animales , Western Blotting , Células Cultivadas , Proteínas de Drosophila/genética , Embrión no Mamífero , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Inmunohistoquímica , Inmunoprecipitación , Fosforilación , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo
8.
J Cell Biol ; 178(4): 557-65, 2007 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-17682050

RESUMEN

The phenylanine-glycine (FG)-rich regions of several nucleoporins both bind to nuclear transport receptors and collectively provide a diffusion barrier to the nuclear pores. However, the in vivo roles of FG nucleoporins in transport remain unclear. We have inactivated 30 putative nucleoporins in cultured Drosophila melanogaster S2 cells by RNA interference and analyzed the phenotypes on importin alpha/beta-mediated import and CRM1-dependent protein export. The fly homologues of FG nucleoporins Nup358, Nup153, and Nup54 are selectively required for import. The FG repeats of Nup153 are necessary for its function in transport, whereas the remainder of the protein maintains pore integrity. Inactivation of the CRM1 cofactor RanBP3 decreased the nuclear accumulation of CRM1 and protein export. We report a surprisingly antagonistic relationship between RanBP3 and the Nup214 FG region in determining CRM1 localization and its function in protein export. Our data suggest that peripheral metazoan FG nucleoporins have distinct functions in nuclear protein transport events.


Asunto(s)
Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismo , Animales , Línea Celular , Drosophila/citología , Proteínas de Drosophila/química , Chaperonas Moleculares/metabolismo , Proteínas de Complejo Poro Nuclear/química , Estructura Terciaria de Proteína , Transporte de Proteínas , Interferencia de ARN
9.
J Cell Sci ; 119(Pt 21): 4409-19, 2006 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-17032737

RESUMEN

CRM1-mediated protein export is an important determinant of the nuclear accumulation of many gene regulators. Here, we show that the NFkappaB transcription factor Dorsal is a substrate of CRM1 and requires the nucleoporin Nup214 for its nuclear translocation upon signaling. Nup214 bound to CRM1 directly and anchored it to the nuclear envelope. In nup214 mutants CRM1 accumulated in the nucleus and NES-protein export was enhanced. Nup214 formed complexes with Nup88 and CRM1 in vivo and Nup214 protected Nup88 from degradation at the nuclear rim. In turn, Nup88 was sufficient for targeting the complex to the nuclear pores. Overexpression experiments indicated that Nup214 alone attracts a fraction of CRM1 to the nuclear envelope but does not interfere with NES-GFP export. By contrast, overexpression of the Nup214-Nup88 complex trapped CRM1 and Dorsal to cytoplasmic foci and inhibited protein export and immune response activation. We hypothesize that variation in levels of the Nup214-Nup88 complex at the pore changes the amount of NPC-bound CRM1 and influences the relative strength and duration of NFkappaB signaling responses.


Asunto(s)
Transporte Activo de Núcleo Celular/fisiología , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Carioferinas/metabolismo , FN-kappa B/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Animales , Western Blotting , Citoplasma/metabolismo , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas Fluorescentes Verdes/metabolismo , Inmunoprecipitación , Carioferinas/antagonistas & inhibidores , Carioferinas/genética , Larva/citología , Larva/metabolismo , Mutagénesis Sitio-Dirigida , Mutación , FN-kappa B/genética , Membrana Nuclear/metabolismo , Señales de Localización Nuclear , Poro Nuclear/metabolismo , Proteínas de Complejo Poro Nuclear/antagonistas & inhibidores , Proteínas de Complejo Poro Nuclear/genética , Transporte de Proteínas , ARN Interferente Pequeño/farmacología , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Proteína Exportina 1
10.
J Cell Biol ; 163(4): 701-6, 2003 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-14638854

RESUMEN

Many cellular responses rely on the control of nucleocytoplasmic transport of transcriptional regulators. The Drosophila nucleoporin Nup88 is selectively required for nuclear accumulation of Rel proteins and full activation of the innate immune response. Here, we investigate the mechanisms underlying its role in nucleocytoplasmic transport. Nuclear import of an nuclear localization signal-enhanced green fluorescent protein (NLS-EGFP) reporter is not affected in DNup88 (members only; mbo) mutants, whereas the level of CRM1-dependent EGFP-nuclear export signal (EGFP-NES) export is increased. We show that the nuclear accumulation of the Drosophila Rel protein Dorsal requires CRM1. DNup88 binds to DNup214 and DCRM1 in vitro, and both proteins become mislocalized from the nuclear rim into the nucleus of mbo mutants. Overexpression of DNup88 is sufficient to relocalize DNup214 and CRM1 on the nuclear envelope and revert the mutant phenotypes. We propose that a major function of DNup88 is to anchor DNup214 and CRM1 on the nuclear envelope and thereby attenuate NES-mediated nuclear export.


Asunto(s)
Transporte Activo de Núcleo Celular/fisiología , Proteínas de Drosophila , Carioferinas/metabolismo , Membrana Nuclear/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismo , Receptores Citoplasmáticos y Nucleares , Factores de Transcripción , Animales , Drosophila , Mutación/genética , Señales de Localización Nuclear/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Recombinantes de Fusión , Proteína Exportina 1
11.
Development ; 129(21): 4941-51, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12397103

RESUMEN

Oxygen delivery in many animals is enabled by the formation of unicellular capillary tubes that penetrate target tissues to facilitate gas exchange. We show that the tortuous outgrowth of tracheal unicellular branches towards their target tissues is controlled by complex local interactions with target cells. Slit, a phylogenetically conserved axonal guidance signal, is expressed in several tracheal targets and is required both for attraction and repulsion of tracheal branches. Robo and Robo2 are expressed in different branches, and are both necessary for the correct orientation of branch outgrowth. At the CNS midline, Slit functions as a repellent for tracheal branches and this function is mediated primarily by Robo. Robo2 is necessary for the tracheal response to the attractive Slit signal and its function is antagonized by Robo. We propose that the attractive and repulsive tracheal responses to Slit are mediated by different combinations of Robo and Robo2 receptors on the cell surface.


Asunto(s)
Proteínas de Drosophila , Drosophila/embriología , Drosophila/fisiología , Proteínas del Tejido Nervioso/fisiología , Tráquea/embriología , Tráquea/fisiología , Animales , Animales Modificados Genéticamente , Sistema Nervioso Central/embriología , Drosophila/genética , Ganglios/embriología , Regulación del Desarrollo de la Expresión Génica , Genes de Insecto , Operón Lac , Proteínas del Tejido Nervioso/genética , Neuroglía/citología , Fenotipo , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Transducción de Señal , Proteínas Roundabout
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