RESUMEN
The Hippo pathway regulates cell proliferation and organ size through control of the transcriptional regulators YAP (yes-associated protein) and TAZ. Upon extracellular stimuli such as cell-cell contact, the pathway negatively regulates YAP through cytoplasmic sequestration. Under conditions of low cell density, YAP is nuclear and associates with enhancer regions and gene promoters. YAP is mainly described as a transcriptional activator of genes involved in cell proliferation and survival. Using a genome-wide approach, we show here that, in addition to its known function as a transcriptional activator, YAP functions as a transcriptional repressor by interacting with the multifunctional transcription factor Yin Yang 1 (YY1) and Polycomb repressive complex member enhancer of zeste homologue 2 (EZH2). YAP colocalized with YY1 and EZH2 on the genome to transcriptionally repress a broad network of genes mediating a host of cellular functions, including repression of the cell-cycle kinase inhibitor p27, whose role is to functionally promote contact inhibition. This work unveils a broad and underappreciated aspect of YAP nuclear function as a transcriptional repressor and highlights how loss of contact inhibition in cancer is mediated in part through YAP repressive function. SIGNIFICANCE: This study provides new insights into YAP as a broad transcriptional repressor of key regulators of the cell cycle, in turn influencing contact inhibition and tumorigenesis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Ciclo Celular/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Neoplasias/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Factor de Transcripción YY1/metabolismo , Animales , Carcinogénesis/genética , Fraccionamiento Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Proliferación Celular/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes/genética , Humanos , Ratones , Neoplasias/patología , Regiones Promotoras Genéticas/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAPRESUMEN
The correct assembly of ribosomes from ribosomal RNAs (rRNAs) and ribosomal proteins (RPs) is critical, as indicated by the diseases caused by RP haploinsufficiency and loss of RP stoichiometry in cancer cells. Nevertheless, how assembly of each RP is ensured remains poorly understood. We use yeast genetics, biochemistry, and structure probing to show that the assembly factor Ltv1 facilitates the incorporation of Rps3, Rps10, and Asc1/RACK1 into the small ribosomal subunit head. Ribosomes from Ltv1-deficient yeast have substoichiometric amounts of Rps10 and Asc1 and show defects in translational fidelity and ribosome-mediated RNA quality control. These defects provide a growth advantage under some conditions but sensitize the cells to oxidative stress. Intriguingly, relative to glioma cell lines, breast cancer cells have reduced levels of LTV1 and produce ribosomes lacking RPS3, RPS10, and RACK1. These data describe a mechanism to ensure RP assembly and demonstrate how cancer cells circumvent this mechanism to generate diverse ribosome populations that can promote survival under stress.
Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Neoplasias/metabolismo , Subunidades Ribosómicas Pequeñas de Eucariotas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Subunidades Ribosómicas Pequeñas de Eucariotas/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Cisplatin-induced nephrotoxicity limits its use in many cancer patients. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI). Using gene knockout and chemical inhibitors, the role of polyamine catabolism in cisplatin AKI was examined. Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and enhances the expression of binding immunoglobulin protein BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of these endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3). These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Antineoplásicos/efectos adversos , Cisplatino/efectos adversos , Estrés del Retículo Endoplásmico , Poliaminas/metabolismo , Acetiltransferasas/metabolismo , Lesión Renal Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Chaperón BiP del Retículo Endoplásmico , Pruebas de Función Renal , Redes y Vías Metabólicas , Ratones , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Índice de Severidad de la Enfermedad , Poliamino OxidasaRESUMEN
Glutamine and tyrosine-based amino acid conjugates of monocarboxylate transporter types 1 and 2 inhibitors (MCT1/2) were designed, synthesized and evaluated for their potency in blocking the proliferation of a human B lymphoma cell line that expresses the transporters Asct2, LAT1 and MCT1. Appropriate placement of an amino acid transporter recognition element was shown to augment anti-tumour efficacy vs. Raji cells. Amino acid conjugation also improves the pharmacodynamic properties of experimental MCT1/2 inhibitors.
RESUMEN
Casein kinase 1δ/ε (CK1δ/ε) and their yeast homologue Hrr25 are essential for cell growth. Further, CK1δ is overexpressed in several malignancies, and CK1δ inhibitors have shown promise in several preclinical animal studies. However, the substrates of Hrr25 and CK1δ/ε that are necessary for cell growth and survival are unknown. We show that Hrr25 is essential for ribosome assembly, where it phosphorylates the assembly factor Ltv1, which causes its release from nascent 40S subunits and allows subunit maturation. Hrr25 inactivation or expression of a nonphosphorylatable Ltv1 variant blocked Ltv1 release in vitro and in vivo, and prevented entry into the translation-like quality control cycle. Conversely, phosphomimetic Ltv1 variants rescued viability after Hrr25 depletion. Finally, Ltv1 knockdown in human breast cancer cells impaired apoptosis induced by CK1δ/ε inhibitors, establishing that the antiproliferative activity of these inhibitors is due, at least in part, to disruption of ribosome assembly. These findings validate the ribosome assembly pathway as a novel target for the development of anticancer therapeutics.
Asunto(s)
Quinasa de la Caseína I/fisiología , Quinasa Idelta de la Caseína/fisiología , Subunidades Ribosómicas Pequeñas de Eucariotas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiología , Saccharomyces cerevisiae/enzimología , Línea Celular Tumoral , Humanos , Proteínas Nucleares/metabolismo , Fosforilación , Unión Proteica , Procesamiento Proteico-Postraduccional , Proteínas Ribosómicas/metabolismo , Saccharomyces cerevisiae/citologíaRESUMEN
Here we report the cloning and functional characterization of the cyclin D-dependent kinase 4 and 6 (Cdk4/6) inhibitory protein Cdkn2d/p19Ink4d of Xenopuslaevis (Xl-Ink4d). Xl-Ink4d is the only Ink4 family gene highly expressed during Xenopus development and its transcripts were detected maternally and during neurulation. The Xl-Ink4d protein has 63% identity to mouse and human Cdkn2d/p19Ink4d and its function as a negative regulator of cell cycle traverse is evolutionary conserved. Indeed, Xl-lnk4d can functionally substitute for mouse Cdkn2d in binding to mouse Cdk4 and inhibiting cyclin-D1-dependent CDK4 kinase activity. Further, enforced expression of Xl-lnk4d arrests mouse fibroblasts in the G1 phase of the cell cycle. These findings indicate that CDKN2d/p19Ink4d is conserved through vertebrate evolution and suggest Xl-lnk4d may contribute to the development of Xenopuslaevis.
RESUMEN
Novel substituted pteridine-derived inhibitors of monocarboxylate transporter 1 (MCT1), an emerging target for cancer therapy, are reported. The activity of these compounds as inhibitors of lactate transport was confirmed using a (14)C-lactate transport assay, and their potency against MCT1-expressing human tumor cells was established using MTT assays. The four most potent compounds showed substantial anticancer activity (EC50 37-150 nM) vs MCT1-expressing human Raji lymphoma cells.
Asunto(s)
Antineoplásicos/farmacología , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Pteridinas/farmacología , Simportadores/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Transporte Biológico/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Ácido Láctico/metabolismo , Células MCF-7 , Ratones , Modelos Químicos , Estructura Molecular , Transportadores de Ácidos Monocarboxílicos/metabolismo , Pteridinas/síntesis química , Pteridinas/química , Relación Estructura-Actividad , Simportadores/metabolismoRESUMEN
Myc oncoproteins induce genes driving aerobic glycolysis, including lactate dehydrogenase-A that generates lactate. Here, we report that Myc controls transcription of the lactate transporter SLC16A1/MCT1 and that elevated MCT1 levels are manifest in premalignant and neoplastic Eµ-Myc transgenic B cells and in human malignancies with MYC or MYCN involvement. Notably, disrupting MCT1 function leads to an accumulation of intracellular lactate that rapidly disables tumor cell growth and glycolysis, provoking marked alterations in glycolytic intermediates, reductions in glucose transport, and in levels of ATP, NADPH, and ultimately, glutathione (GSH). Reductions in GSH then lead to increases in hydrogen peroxide, mitochondrial damage, and ultimately, cell death. Finally, forcing glycolysis by metformin treatment augments this response and the efficacy of MCT1 inhibitors, suggesting an attractive combination therapy for MYC/MCT1-expressing malignancies.
Asunto(s)
Glutatión/biosíntesis , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Simportadores/genética , Animales , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica/genética , Análisis por Conglomerados , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucólisis/efectos de los fármacos , Glucólisis/genética , Homeostasis/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/farmacología , Metformina/farmacología , Ratones , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Oxidación-Reducción , Fosforilación Oxidativa/efectos de los fármacos , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Simportadores/antagonistas & inhibidores , Simportadores/metabolismo , Transcripción GenéticaRESUMEN
Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.
Asunto(s)
Antineoplásicos/farmacología , Ácido Láctico/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Transporte Biológico , Homeostasis , Humanos , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , Terapia Molecular Dirigida , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/metabolismo , Neoplasias/metabolismoRESUMEN
Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis.
Asunto(s)
Genes Supresores de Tumor , Linfoma de Células B/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Tristetraprolina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Linfocitos B/metabolismo , Línea Celular Tumoral , Transformación Celular Neoplásica , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Estabilidad del ARN , ARN Mensajero/químicaRESUMEN
Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function.
Asunto(s)
Linfocitos B/patología , Regulación Enzimológica de la Expresión Génica/fisiología , Linfoma de Células B/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Animales , Apoptosis , Aurora Quinasa A , Aurora Quinasa B , Aurora Quinasas , Linfocitos B/metabolismo , Células 3T3 BALB , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Proliferación Celular , Transformación Celular Neoplásica , Células Cultivadas , Inmunoprecipitación de Cromatina , Ensayo de Cambio de Movilidad Electroforética , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Luciferasas/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransfecciónRESUMEN
Transposon-based integration systems have been widely used for genetic manipulation of invertebrate and plant model systems. In the past decade, these powerful tools have begun to be used in vertebrates for transgenesis, insertional mutagenesis, and gene therapy applications. Sleeping Beauty (SB) is a member of Tc1/mariner class of transposases and is derived from an inactive form of the gene isolated from Atlantic salmon. SB has been used extensively in human cell lines and in whole animal vertebrate model systems such as the mouse, rat, and zebrafish. In this study, we describe the use of SB in the diploid frog Xenopus tropicalis to generate stable transgenic lines. SB transposon transgenes integrate into the X. tropicalis genome by a noncanonical process and are passed through the germline. We compare the activity of SB in this model organism with that of Tol2, a hAT (hobo, Ac1, TAM)-like transposon system.
Asunto(s)
Transposasas/genética , Xenopus/embriología , Xenopus/genética , Animales , Elementos Transponibles de ADN/fisiología , Embrión no Mamífero , Femenino , Técnicas de Transferencia de Gen , Mutación de Línea Germinal/fisiología , Humanos , Masculino , Modelos Biológicos , Mutagénesis Insercional/fisiología , Transposasas/fisiología , Xenopus/crecimiento & desarrolloRESUMEN
Mix-related homeodomain proteins are involved in endoderm formation in the early vertebrate embryo. We used a yeast two-hybrid screen to identify proteins that interact with Mix.3/mixer to regulate endoderm induction. We demonstrate that cyclin-dependent kinase 9 (CDK9) interacts with the carboxyl terminal domain of Mix.3. CDK9 is the catalytic subunit of the PTEF-b transcription elongation complex that phosphorylates the C-terminal domain of RNA polymerase II to promote efficient elongation of nascent transcripts. Using whole embryo transcription reporter and animal pole explant assays, we show that Mix.3 activity is regulated by CDK9/cyclin complexes. Co-expression of cyclin T2 and cyclin K had different effects on Mix.3 transcriptional activity and endoderm induction. Our data suggest that binding of CDK9, and the recruitment of different cyclin partners, can modulate the endoderm-inducing activity of Mix.3 during embryonic development. Developmental Dynamics 238:1346-1357, 2009. (c) 2009 Wiley-Liss, Inc.
Asunto(s)
Quinasa 9 Dependiente de la Ciclina/metabolismo , Ciclinas/metabolismo , Inducción Embrionaria , Endodermo/fisiología , Proteínas de Homeodominio/metabolismo , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismo , Proteínas de Xenopus/metabolismo , Secuencia de Aminoácidos , Animales , Quinasa 9 Dependiente de la Ciclina/genética , Ciclinas/genética , Proteínas Fetales/genética , Proteínas Fetales/metabolismo , Genes Reporteros , Proteínas de Homeodominio/genética , Hibridación in Situ , Datos de Secuencia Molecular , Unión Proteica , Isoformas de Proteínas/genética , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Factores de Transcripción/genética , Técnicas del Sistema de Dos Híbridos , Proteínas de Xenopus/genética , Xenopus laevis/anatomía & histología , Xenopus laevis/embriología , Xenopus laevis/metabolismoRESUMEN
We have used the Sleeping Beauty (SB) transposable element to generate transgenic Xenopus laevis with expression of green fluorescent protein (GFP) in vascular endothelial cells using the frog flk-1 promoter. This is the first characterization of a SB-generated transgenic Xenopus that has tissue-restricted expression. We demonstrate that the transgene integrated into single genomic loci in two independent founder lines and is transmitted through the germline at the expected Mendelian frequencies. Transgene integration occurred through a noncanonical transposition process possibly reflecting Xenopus-specific interactions with the SB system. The transgenic animals express GFP in the same spatial and temporal pattern as the endogenous flk-1 gene throughout development and into adulthood. Overexpression of xVEGF122 in the transgenic animals disrupts vascular development that is visualized by fluorescent microscopy. These studies demonstrate the convenience of the SB system for generating transgenic animals and the utility of the xflk-1:GFP transgenic line for in vivo studies of vascular development.
Asunto(s)
Vasos Sanguíneos/embriología , Elementos Transponibles de ADN , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Xenopus laevis , Animales , Animales Modificados Genéticamente , Vasos Sanguíneos/citología , Vasos Sanguíneos/metabolismo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Modelos Animales , Regiones Promotoras Genéticas , Transgenes , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Xenopus laevis/embriología , Xenopus laevis/genética , Xenopus laevis/metabolismoRESUMEN
The Mix/Bix family of Pax-like homeodomain transcription factors is expressed early in vertebrate development and play important roles in endoderm and mesoderm formation. Like other Pax-related homeodomain proteins, the Mix/Bix family binds DNA as monomers or dimers and dimerization is mediated by the homeodomain. While the Mix/Bix family shares extensive sequence homology within the DNA-binding homeodomain, ectopic expression of these proteins has profoundly different outcomes. Expression of Xenopus Mix.3/Mixer in explanted ectoderm results in endoderm differentiation, whereas Mix.1 expression does not. In this study we sought to define the domains of Mix.3/Mixer that are responsible for this endoderm inducing activity. We generated domain swap mutants between Mix.3/Mixer and Mix.1 and tested their ability to induce endoderm in explanted ectoderm. We demonstrate that the homeodomain and sixty-two amino acids in the carboxyl terminus are required to induce endoderm and that these domains must be on the same polypeptide and can not act in trans as a heterodimer. A Smad2 interaction motif in Mix.3/Mixer is involved in endoderm differentiation but is not essential. Thus, we have defined the regions of Mix.3/Mixer that confer endoderm-inducing activity. These studies reveal a novel co-operation between the homeodomain and a small domain in the carboxyl terminal region that is essential for Mix.3/Mixer function.
Asunto(s)
Endodermo/metabolismo , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismo , Proteínas de Xenopus/química , Proteínas de Xenopus/metabolismo , Animales , Secuencia de Bases , ADN/genética , ADN/metabolismo , Inducción Embrionaria , Proteínas Fetales/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Mutagénesis , Unión Proteica , Estructura Terciaria de Proteína , Proteína Smad2/metabolismo , Proteínas de Dominio T Box/genética , Factores de Transcripción/genética , Proteínas de Xenopus/genética , Xenopus laevis/embriología , Xenopus laevis/genética , Xenopus laevis/metabolismoRESUMEN
The suppressor of cytokine signaling (SOCS) family of proteins are intracellular mediators of cytokine signaling. These proteins are induced rapidly by cytokine stimulation and act in a classic negative-feedback loop to attenuate the cellular response to the cytokine signal. In this study, we present the cloning and initial characterization of the Xenopus SOCS3 gene. We show that xSOCS3 is rapidly induced in response to epithelial wounding in the tadpole. The induction of xSOCS3 in response to trauma is transient with maximal expression being reached 1 hr after the injury and diminishing after that. Unlike other genes known to be responsive to wound-induced activation of the mitogen-activated protein (MAP) kinase pathway, such as Egr1, SOCS3 expression in response to trauma is unaffected by blockade of the MAP kinase pathway by chemical inhibitors.