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1.
J Immunol ; 191(7): 3568-77, 2013 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-24006460

RESUMEN

The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.


Asunto(s)
Inflamación/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Triazoles/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Silenciador del Gen , Humanos , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Interleucina-6/farmacología , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Masculino , Ratones , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Ratas , Factor de Transcripción STAT1/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/inmunología , Triazoles/administración & dosificación
2.
Nat Commun ; 15(1): 6430, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-39080267

RESUMEN

Parkinson's disease is highly heterogeneous across disease symptoms, clinical manifestations and progression trajectories, hampering the identification of therapeutic targets. Despite knowledge gleaned from genetics analysis, dysregulated proteome mechanisms stemming from genetic aberrations remain underexplored. In this study, we develop a three-phase system-level proteogenomic analytical framework to characterize disease-associated proteins and dysregulated mechanisms. Proteogenomic analysis identified 577 proteins that enrich for Parkinson's disease-related pathways, such as cytokine receptor interactions and lysosomal function. Converging lines of evidence identified nine proteins, including LGALS3, CSNK2A1, SMPD3, STX4, APOA2, PAFAH1B3, LDLR, HSPB1, BRK1, with potential roles in disease pathogenesis. This study leverages the largest population-scale proteomics dataset, the UK Biobank Pharma Proteomics Project, to characterize genetically-driven protein disturbances associated with Parkinson's disease. Taken together, our work contributes to better understanding of genome-proteome dynamics in Parkinson's disease and sets a paradigm to identify potential indirect mediators connected to GWAS signals for complex neurodegenerative disorders.


Asunto(s)
Enfermedad de Parkinson , Proteogenómica , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Humanos , Proteogenómica/métodos , Proteoma/metabolismo , Estudio de Asociación del Genoma Completo , Proteómica/métodos , Masculino , Femenino
3.
Biochem J ; 434(2): 243-51, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21143198

RESUMEN

When starved of P(i), yeast cells activate the PHO signalling pathway, wherein the Pho4 transcription factor mediates expression of genes involved in P(i) acquisition, such as PHO84, encoding the high-affinity H(+)/P(i) symporter. In contrast, transcription of PHO87 and PHO90, encoding the low-affinity H(+)/P(i) transport system, is independent of phosphate status. In the present work, we reveal that, upon P(i) starvation, these low-affinity P(i) transporters are endocytosed and targeted to the vacuole. For Pho87, this process strictly depends on SPL2, another Pho4-dependent gene that encodes a protein known to interact with the N-terminal SPX domain of the transporter. In contrast, the vacuolar targeting of Pho90 upon Pi starvation is independent of both Pho4 and Spl2, although it still requires its SPX domain. Furthermore, both Pho87 and Pho90 are also targeted to the vacuole upon carbon-source starvation or upon treatment with rapamycin, which mimics nitrogen starvation, but although these responses are independent of PHO pathway signalling, they again require the N-terminal SPX domain of the transporters. These observations suggest that other SPX-interacting proteins must be involved. In addition, we show that Pho90 is the most important P(i) transporter under high P(i) conditions in the absence of a high-affinity P(i)-transport system. Taken together, our results illustrate that Pho87 and Pho90 represent non-redundant P(i) transporters, which are tuned by the integration of multiple nutrient signalling mechanisms in order to adjust P(i)-transport capacity to the general nutritional status of the environment.


Asunto(s)
Proteínas de Transporte de Fosfato/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Transporte Biológico , Endocitosis , Proteínas de Transporte de Fosfato/genética , Fosfatos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Transducción de Señal
4.
Curr Genet ; 56(1): 1-32, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20054690

RESUMEN

Cells of all living organisms contain complex signal transduction networks to ensure that a wide range of physiological properties are properly adapted to the environmental conditions. The fundamental concepts and individual building blocks of these signalling networks are generally well-conserved from yeast to man; yet, the central role that growth factors and hormones play in the regulation of signalling cascades in higher eukaryotes is executed by nutrients in yeast. Several nutrient-controlled pathways, which regulate cell growth and proliferation, metabolism and stress resistance, have been defined in yeast. These pathways are integrated into a signalling network, which ensures that yeast cells enter a quiescent, resting phase (G0) to survive periods of nutrient scarceness and that they rapidly resume growth and cell proliferation when nutrient conditions become favourable again. A series of well-conserved nutrient-sensory protein kinases perform key roles in this signalling network: i.e. Snf1, PKA, Tor1 and Tor2, Sch9 and Pho85-Pho80. In this review, we provide a comprehensive overview on the current understanding of the signalling processes mediated via these kinases with a particular focus on how these individual pathways converge to signalling networks that ultimately ensure the dynamic translation of extracellular nutrient signals into appropriate physiological responses.


Asunto(s)
Fenómenos Fisiológicos de la Nutrición/fisiología , Saccharomyces cerevisiae/fisiología , Transducción de Señal , Proteínas Quinasas/metabolismo , Proteínas Quinasas/fisiología
6.
FEBS Lett ; 580(7): 1903-7, 2006 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-16527275

RESUMEN

The antifungal plant defensin DmAMP1 interacts with fungal sphingolipids of mannosyldiinositolphosphorylceramide (M(IP)2C) class. We screened a Saccharomyces cerevisiae transposon (Tn) mutant library against DmAMP1 and identified one DmAMP1-resistant mutant with the Tn inserted in the M(IP)2C biosynthesis gene IPT1 (DmTn11) and one DmAMP1-hypersensitive mutant with the Tn inserted in rDNA (HsTnII). However, tetrad analysis pointed to HsTnII as a spontaneous mutant. Apparently, membranes of DmTn11 lack M(IP)2C, whereas membranes of HsTnII have increased M(IP)2C levels. In addition, DmTn11 and HsTnII are characterized by increased and reduced oxidative stress resistance/chronological life-span (CL), respectively. A putative involvement of M(IP)2C in oxidative stress and CL in yeast is discussed.


Asunto(s)
Defensinas/fisiología , Glicoesfingolípidos/fisiología , Estrés Oxidativo , Oxígeno/metabolismo , Levaduras/citología , Glicoesfingolípidos/análisis , Mutación , Plantas/inmunología , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética
7.
PLoS One ; 10(12): e0144428, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26714269

RESUMEN

As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.


Asunto(s)
Canales Iónicos/genética , MicroARNs/genética , Neurotransmisores/genética , Esquizofrenia/genética , Línea Celular Tumoral , Perfilación de la Expresión Génica , Genómica , Humanos , Mutación , Especificidad de Órganos
8.
Mol Biol Cell ; 25(1): 196-211, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24196832

RESUMEN

The Saccharomyces cerevisiae protein kinase Sch9 is an in vitro and in vivo effector of sphingolipid signaling. This study examines the link between Sch9 and sphingolipid metabolism in S. cerevisiae in vivo based on the observation that the sch9Δ mutant displays altered sensitivity to different inhibitors of sphingolipid metabolism, namely myriocin and aureobasidin A. Sphingolipid profiling indicates that sch9Δ cells have increased levels of long-chain bases and long-chain base-1 phosphates, decreased levels of several species of (phyto)ceramides, and altered ratios of complex sphingolipids. We show that the target of rapamycin complex 1-Sch9 signaling pathway functions to repress the expression of the ceramidase genes YDC1 and YPC1, thereby revealing, for the first time in yeast, a nutrient-dependent transcriptional mechanism involved in the regulation of sphingolipid metabolism. In addition, we establish that Sch9 affects the activity of the inositol phosphosphingolipid phospholipase C, Isc1, which is required for ceramide production by hydrolysis of complex sphingolipids. Given that sphingolipid metabolites play a crucial role in the regulation of stress tolerance and longevity of yeast cells, our data provide a model in which Sch9 regulates the latter phenotypes by acting not only as an effector but also as a regulator of sphingolipid metabolism.


Asunto(s)
Ceramidas/biosíntesis , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Antifúngicos/farmacología , Depsipéptidos/farmacología , Farmacorresistencia Fúngica , Ácidos Grasos Monoinsaturados/farmacología , Regulación Fúngica de la Expresión Génica , Técnicas de Inactivación de Genes , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana , Proteínas Serina-Treonina Quinasas/genética , Transporte de Proteínas , Saccharomyces cerevisiae/efectos de los fármacos , Proteínas de Saccharomyces cerevisiae/genética , Esfingolípidos/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacología , Transcripción Genética , Fosfolipasas de Tipo C/metabolismo
9.
FEMS Yeast Res ; 8(8): 1276-88, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18759743

RESUMEN

The protein kinase Sch9 is proposed to be a downstream effector of TORC1 that is required for activation of ribosome biogenesis and repression of entry into G(0). However, Sch9 apparently functions antagonistically to TORC1, when considering the induction of several stress defence genes that are normally repressed by TORC1. To further investigate the relationship between Sch9 and TORC1, we compared the rapamycin-induced transcriptional responses in an sch9Delta mutant and the isogenic wild type. The data indicate that Sch9 is necessary for proper integration of the rapamycin-induced stress signal, i.e. in sch9Delta cells, typical effects of rapamycin-like repression of ribosomal protein genes and induction of stress response genes are diminished or abolished. Moreover, they reveal for the first time a direct link between Sch9 and nitrogen metabolism. A sch9Delta mutant has an increased basal activation of targets of the general amino acid control pathway and of the nitrogen discrimination pathway, including the ammonium permease MEP2 and the amino acid permease GAP1. The mutant also shows enhanced expression of the transcription factor Gcn4 required for amino acid biosynthesis. Our data favour a model in which (1) the role of Sch9 in the general stress response switches depending on TORC1 activity and (2) Sch9 and TORC1 have independent and additive effects on genes induced upon nitrogen and amino acid starvation.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Genoma Fúngico , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Antifúngicos/farmacología , Proteínas de Ciclo Celular/genética , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica , Fosfatidilinositol 3-Quinasas/genética , Proteínas Quinasas/genética , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Proteínas de Saccharomyces cerevisiae/genética , Sirolimus/farmacología
10.
Genome Biol ; 7(5): R37, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16677396

RESUMEN

'ReMoDiscovery' is an intuitive algorithm to correlate regulatory programs with regulators and corresponding motifs to a set of co-expressed genes. It exploits in a concurrent way three independent data sources: ChIP-chip data, motif information and gene expression profiles. When compared to published module discovery algorithms, ReMoDiscovery is fast and easily tunable. We evaluated our method on yeast data, where it was shown to generate biologically meaningful findings and allowed the prediction of potential novel roles of transcriptional regulators.


Asunto(s)
Algoritmos , Inmunoprecipitación de Cromatina , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Aminoácidos/metabolismo , Ciclo Celular , Galactosa/metabolismo , Elementos Reguladores de la Transcripción , Ribosomas/metabolismo , Programas Informáticos , Factores de Transcripción/metabolismo , Levaduras/genética , Levaduras/crecimiento & desarrollo , Levaduras/metabolismo
11.
Cell Div ; 1: 3, 2006 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-16759348

RESUMEN

In recent years, the general understanding of nutrient sensing and signalling, as well as the knowledge about responses triggered by altered nutrient availability have greatly advanced. While initial studies were directed to top-down elucidation of single nutrient-induced pathways, recent investigations place the individual signalling pathways into signalling networks and pursue the identification of converging effector branches that orchestrate the dynamical responses to nutritional cues. In this review, we focus on Rim15, a protein kinase required in yeast for the proper entry into stationary phase (G0). Recent studies revealed that the activity of Rim15 is regulated by the interplay of at least four intercepting nutrient-responsive pathways.

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