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1.
Commun Biol ; 3(1): 642, 2020 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-33144666

RESUMEN

The liver and gallbladder are among the most important internal organs derived from the endoderm, yet the development of the liver and gallbladder in the early embryonic stages is not fully understood. Using a transgenic Foxa2eGFP reporter mouse line, we performed single-cell full-length mRNA sequencing on endodermal and hepatic cells isolated from ten embryonic stages, ranging from E7.5 to E15.5. We identified the embryonic liver developmental trajectory from gut endoderm to hepatoblasts and characterized the transcriptome of the hepatic lineage. More importantly, we identified liver primordium as the nascent hepatic progenitors with both gut and liver features and documented dynamic gene expression during the epithelial-hepatic transition (EHT) at the stage of liver specification during E9.5-11.5. We found six groups of genes switched on or off in the EHT process, including diverse transcripitional regulators that had not been previously known to be expressed during EHT. Moreover, we identified and revealed transcriptional profiling of gallbladder primordium at E9.5. The present data provides a high-resolution resource and critical insights for understanding the liver and gallbladder development.


Asunto(s)
Factor Nuclear 3-beta del Hepatocito/metabolismo , Hígado/embriología , Animales , Células Cultivadas , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Factor Nuclear 3-beta del Hepatocito/genética , Hígado/metabolismo , Ratones , Análisis de Secuencia de ARN , Análisis de la Célula Individual
2.
Stem Cells Int ; 2018: 8632950, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30254684

RESUMEN

Studies have demonstrated that STAT3 is essential in maintaining self-renewal of embryonic stem cells (ESCs) and modulates ESC differentiation. However, there is still lack of direct evidence on STAT3 functions in ESCs and embryogenesis because constitutive STAT3 knockout (KO) mouse is embryonic lethal at E6.5-E7.5, prior to potential functional role in early development can be assessed. Therefore, in this study, two inducible STAT3 ESC lines were established, including the STAT3 knockout (InSTAT3 KO) and pSTAT3 overexpressed (InSTAT3 CA) using Tet-on inducible system in which STAT3 expression can be strictly controlled by doxycycline (Dox) stimulation. Through genotyping, deletion of STAT3 alleles was detected in InSTAT3 KO ESCs following 24 hours Dox stimulation. Western blot also showed that pSTAT3 and STAT3 protein levels were significantly reduced in InSTAT3 KO ESCs while dominantly elevated in InSTAT3 CA ECSs upon Dox stimulation. Likewise, it was found that STAT3-null ESCs would affect the differentiation of ESCs into mesoderm and cardiac lineage. Taken together, the findings of this study indicated that InSTAT3 KO and InSTAT3 CA ESCs could provide a new tool to clarify the direct targets of STAT3 and its role in ESC maintenance, which will facilitate the elaboration of the mechanisms whereby STAT3 maintains ESC pluripotency and regulates ESC differentiation during mammalian embryogenesis.

3.
Mol Cell Biol ; 24(19): 8447-56, 2004 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-15367666

RESUMEN

Mitochondria play essential roles in cellular energy production via the oxidative phosphorylation system (OXPHOS) consisting of five multiprotein complexes and also in the initiation of apoptosis. NADH:ubiquinone oxidoreductase (complex I) is the largest complex that catalyzes the first step of electron transfer in the OXPHOS system. GRIM-19 was originally identified as a nuclear protein with apoptotic nature in interferon (IFN)- and all-trans-retinoic acid (RA)-induced tumor cells. To reveal its biological role, we generated mice deficient in GRIM-19 by gene targeting. Homologous deletion of GRIM-19 causes embryonic lethality at embryonic day 9.5. GRIM-19(-/-) blastocysts show retarded growth in vitro and, strikingly, display abnormal mitochondrial structure, morphology, and cellular distribution. We reexamined the cellular localization of GRIM-19 in various cell types and found its primary localization in the mitochondria. Furthermore, GRIM-19 is detected in the native form of mitochondrial complex I. Finally, we show that elimination of GRIM-19 destroys the assembly and electron transfer activity of complex I and also influences the other complexes in the mitochondrial respiratory chain. Our result demonstrates that GRIM-19, a gene product with a specific role in IFN-RA-induced cell death, is a functional component of mitochondrial complex I and is essential for early embryonic development.


Asunto(s)
Complejo I de Transporte de Electrón/metabolismo , Mitocondrias/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Animales , Apoptosis/genética , Apoptosis/fisiología , Blastocisto/patología , División Celular/genética , División Celular/fisiología , Ratones , Ratones Noqueados , Microscopía Confocal , Mitocondrias/patología , NADH NADPH Oxidorreductasas/deficiencia , NADH NADPH Oxidorreductasas/genética , Eliminación de Secuencia
4.
FEBS Lett ; 583(2): 271-6, 2009 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-19084525

RESUMEN

Pin1 actively regulates diverse biological/pathological processes, but little is known about the regulatory mechanisms of its cellular localization. In this study, we report that the endogenous Pin1 is distributed in both nucleus and cytoplasm. We found that point mutations of several basic amino acids in the PPIase domain of Pin1 significantly compromise its nuclear localization. Such inhibition is independent of Pin1 enzymatic activity, and is mainly due to the defects in the nuclear import. A novel sequence harboring these residues was identified as a putative nuclear localization signal (NLS) of Pin1. Importin alpha5 of the nuclear import machinery was found to interact with Pin1.


Asunto(s)
Núcleo Celular/enzimología , Señales de Localización Nuclear/metabolismo , Isomerasa de Peptidilprolil/metabolismo , Transporte Activo de Núcleo Celular , Secuencia de Aminoácidos , Arginina/genética , Arginina/metabolismo , Citoplasma/enzimología , Células HeLa , Humanos , Carioferinas/genética , Carioferinas/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA , Señales de Localización Nuclear/genética , Isomerasa de Peptidilprolil/genética , Mutación Puntual , Estructura Terciaria de Proteína , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Proteína Exportina 1
5.
EMBO J ; 22(6): 1325-35, 2003 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-12628925

RESUMEN

Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic transcription factor that can be activated by cytokines and growth factors. Stat3 plays important roles in cell growth, anti-apoptosis and cell transformation, and is constitutively active in various cancers. We examined its potential regulators by yeast two-hybrid screening. GRIM-19, a gene product related to interferon-beta- and retinoic acid-induced cancer cell death, was identified and demonstrated to interact with Stat3 in various cell types. The interaction is specific for Stat3, but not for Stat1 and Stat5a. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. GRIM-19 itself co-localizes with mitochondrial markers, and forms aggregates at the perinulear region with co-expressed Stat3, which inhibits Stat3 nuclear translocation stimulated by epidermal growth factor (EGF). GRIM-19 represses Stat3 transcriptional activity and its target gene expression, and also suppresses cell growth in Src-transformed cells and a Stat3-expressing cell line. Our data suggest that GRIM-19 is a novel negative regulator of Stat3.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Chaperonas Moleculares/metabolismo , Transactivadores/metabolismo , Células 3T3 , Animales , Proteínas Reguladoras de la Apoptosis , Células COS , División Celular/efectos de los fármacos , Línea Celular Transformada , Chlorocebus aethiops , Complejo I de Transporte de Electrón/química , Complejo I de Transporte de Electrón/genética , Factor de Crecimiento Epidérmico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Humanos , Interferón beta/farmacología , Ratones , Mitocondrias/química , Chaperonas Moleculares/química , Chaperonas Moleculares/genética , Mutación , NADH NADPH Oxidorreductasas , Células PC12 , Estructura Terciaria de Proteína , Ratas , Proteínas Recombinantes/metabolismo , Factor de Transcripción STAT3 , Transcripción Genética , Tretinoina/farmacología
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