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1.
Cell ; 187(13): 3409-3426.e24, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38744281

RESUMEN

Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.


Asunto(s)
Linfocitos T CD8-positivos , Factores de Transcripción , Animales , Femenino , Humanos , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Matriz Extracelular/metabolismo , Histona Desacetilasas/metabolismo , Ratones Endogámicos C57BL , Neoplasias/inmunología , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Agotamiento de Células T , Factores de Transcripción/metabolismo , Microambiente Tumoral , Estrés Mecánico
2.
Cell ; 184(22): 5559-5576.e19, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34678143

RESUMEN

Glucose consumption is generally increased in tumor cells to support tumor growth. Interestingly, we report that glycogen accumulation is a key initiating oncogenic event during liver malignant transformation. We found that glucose-6-phosphatase (G6PC) catalyzing the last step of glycogenolysis is frequently downregulated to augment glucose storage in pre-malignant cells. Accumulated glycogen undergoes liquid-liquid phase separation, which results in the assembly of the Laforin-Mst1/2 complex and consequently sequesters Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme-liver glycogen phosphorylase (PYGL) deficiency in both human and mice results in glycogen storage disease along with liver enlargement and tumorigenesis in a Yap-dependent manner. Consistently, elimination of glycogen accumulation abrogates liver growth and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that cancer-initiating cells adapt a glycogen storing mode, which blocks Hippo signaling through glycogen phase separation to augment tumor incidence.


Asunto(s)
Carcinogénesis/metabolismo , Carcinogénesis/patología , Glucógeno/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Glucosa-6-Fosfatasa/metabolismo , Glucógeno Fosforilasa/metabolismo , Factor de Crecimiento de Hepatocito/metabolismo , Vía de Señalización Hippo , Humanos , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Estadificación de Neoplasias , Transición de Fase , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Serina-Treonina Quinasa 3/metabolismo , Proteínas Señalizadoras YAP/metabolismo
3.
Nat Immunol ; 19(9): 1036, 2018 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-29449628

RESUMEN

In the version of this article initially published, the institution name for affiliation 3 (Maryland Anderson Cancer Center) was incorrect. The correct institution is MD Anderson Cancer Center. The error has been corrected in the HTML and PDF versions of the article.

4.
Mol Cell ; 82(10): 1850-1864.e7, 2022 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-35429439

RESUMEN

YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Transducción de Señal , Carcinogénesis , Vía de Señalización Hippo , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Proteínas Supresoras de Tumor/metabolismo
5.
Nat Immunol ; 18(7): 800-812, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28504697

RESUMEN

An imbalance in the lineages of immunosuppressive regulatory T cells (Treg cells) and the inflammatory TH17 subset of helper T cells leads to the development of autoimmune and/or inflammatory disease. Here we found that TAZ, a coactivator of TEAD transcription factors of Hippo signaling, was expressed under TH17 cell-inducing conditions and was required for TH17 differentiation and TH17 cell-mediated inflammatory diseases. TAZ was a critical co-activator of the TH17-defining transcription factor RORγt. In addition, TAZ attenuated Treg cell development by decreasing acetylation of the Treg cell master regulator Foxp3 mediated by the histone acetyltransferase Tip60, which targeted Foxp3 for proteasomal degradation. In contrast, under Treg cell-skewing conditions, TEAD1 expression and sequestration of TAZ from the transcription factors RORγt and Foxp3 promoted Treg cell differentiation. Furthermore, deficiency in TAZ or overexpression of TEAD1 induced Treg cell differentiation, whereas expression of a transgene encoding TAZ or activation of TAZ directed TH17 cell differentiation. Our results demonstrate a pivotal role for TAZ in regulating the differentiation of Treg cells and TH17 cells.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Diferenciación Celular/inmunología , Colitis/inmunología , Citocinas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Péptidos y Proteínas de Señalización Intracelular/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Acetilación , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/inmunología , Proteínas de Unión al ADN/metabolismo , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Células HEK293 , Células HeLa , Histona Acetiltransferasas/metabolismo , Humanos , Immunoblotting , Lisina Acetiltransferasa 5 , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía Confocal , Microscopía Fluorescente , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT3/metabolismo , Síndrome de Sjögren/inmunología , Proteínas Smad/inmunología , Proteínas Smad/metabolismo , Factores de Transcripción de Dominio TEA , Transactivadores/metabolismo , Factores de Transcripción/inmunología , Factores de Transcripción/metabolismo , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ
7.
Mol Cell ; 78(6): 1192-1206.e10, 2020 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-32470318

RESUMEN

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.


Asunto(s)
Proteínas Portadoras/metabolismo , Micropartículas Derivadas de Células/metabolismo , Proteínas de la Membrana/metabolismo , Hormonas Tiroideas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas Portadoras/genética , Diferenciación Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Micropartículas Derivadas de Células/genética , Micropartículas Derivadas de Células/patología , Quimiocina CCL1/metabolismo , Progresión de la Enfermedad , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Monocitos/metabolismo , Pronóstico , Factor de Transcripción STAT3/metabolismo , Hormonas Tiroideas/genética , Microambiente Tumoral , Proteínas de Unión a Hormona Tiroide
8.
Nat Immunol ; 16(11): 1142-52, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26414765

RESUMEN

Mitochondria need to be juxtaposed to phagosomes for the synergistic production of ample reactive oxygen species (ROS) in phagocytes to kill pathogens. However, how phagosomes transmit signals to recruit mitochondria has remained unclear. Here we found that the kinases Mst1 and Mst2 functioned to control ROS production by regulating mitochondrial trafficking and mitochondrion-phagosome juxtaposition. Mst1 and Mst2 activated the GTPase Rac to promote Toll-like receptor (TLR)-triggered assembly of the TRAF6-ECSIT complex that is required for the recruitment of mitochondria to phagosomes. Inactive forms of Rac, including the human Rac2(D57N) mutant, disrupted the TRAF6-ECSIT complex by sequestering TRAF6 and substantially diminished ROS production and enhanced susceptibility to bacterial infection. Our findings demonstrate that the TLR-Mst1-Mst2-Rac signaling axis is critical for effective phagosome-mitochondrion function and bactericidal activity.


Asunto(s)
Fagocitos/inmunología , Fagocitos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Infecciones Bacterianas/etiología , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/metabolismo , Actividad Bactericida de la Sangre/inmunología , Línea Celular , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos de Histocompatibilidad Menor , Mitocondrias/inmunología , Mitocondrias/metabolismo , Mitocondrias/microbiología , Fagocitos/microbiología , Fagosomas/inmunología , Fagosomas/metabolismo , Fagosomas/microbiología , Proteína Quinasa C-alfa/metabolismo , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Sepsis/etiología , Sepsis/inmunología , Sepsis/metabolismo , Serina-Treonina Quinasa 3 , Transducción de Señal , Factor 6 Asociado a Receptor de TNF , Receptores Toll-Like/metabolismo , Ubiquitinación , Proteínas de Unión al GTP rac/genética , Proteínas de Unión al GTP rac/metabolismo , Inhibidor beta de Disociación del Nucleótido Guanina rho/metabolismo
9.
Cell ; 144(5): 782-95, 2011 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-21376238

RESUMEN

During development and regeneration, proliferation of tissue-specific stem cells is tightly controlled to produce organs of a predetermined size. The molecular determinants of this process remain poorly understood. Here, we investigate the function of Yap1, the transcriptional effector of the Hippo signaling pathway, in skin biology. Using gain- and loss-of-function studies, we show that Yap1 is a critical modulator of epidermal stem cell proliferation and tissue expansion. Yap1 mediates this effect through interaction with TEAD transcription factors. Additionally, our studies reveal that α-catenin, a molecule previously implicated in tumor suppression and cell density sensing in the skin, is an upstream negative regulator of Yap1. α-catenin controls Yap1 activity and phosphorylation by modulating its interaction with 14-3-3 and the PP2A phosphatase. Together, these data identify Yap1 as a determinant of the proliferative capacity of epidermal stem cells and as an important effector of a "crowd control" molecular circuitry in mammalian skin.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proliferación Celular , Células Epidérmicas , Fosfoproteínas/metabolismo , alfa Catenina/metabolismo , Proteínas 14-3-3/metabolismo , Animales , Proteínas de Ciclo Celular , Línea Celular , Epidermis/metabolismo , Ratones , Proteínas Señalizadoras YAP
10.
J Lipid Res ; 64(10): 100440, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37826876

RESUMEN

Neonates strive to acquire energy when the continuous transplacental nutrient supply ceases at birth, whereas milk consumption takes hours to start. Using murine models, we report the metabolic switches in the first days of life, with an unexpected discovery of glucose as the universal fuel essential for neonatal life. Blood glucose quickly drops as soon as birth, but immediately rebounds even before suckling and maintains stable afterward. Meanwhile, neonatal liver undergoes drastic metabolic changes, from extensive glycogenolysis before suckling to dramatically induced fatty acid oxidation (FAO) and gluconeogenesis after milk suckling. Unexpectedly, blocking hepatic glycogenolysis only caused a transient hypoglycemia before milk suckling without causing lethality. Limiting lipid supply in milk (low-fat milk, [LFM]) using Cidea-/- mice, however, led to a chronic and severe hypoglycemia and consequently claimed neonatal lives. While fat replenishment rescued LFM-caused neonatal lethality, the rescue effects were abolished by blocking FAO or gluconeogenesis, pointing to a funneling of lipids and downstream metabolites into glucose as the essential fuel. Finally, glucose administration also rescued LFM-caused neonatal lethality, independent on FAO or gluconeogenesis. Therefore, our results show that the liver works as an energy conversion center to maintain blood glucose homeostasis in neonates, providing theoretical basis for managing infant hypoglycemia.


Asunto(s)
Glucemia , Hipoglucemia , Humanos , Animales , Ratones , Animales Recién Nacidos , Glucemia/metabolismo , Glucógeno/metabolismo , Gluconeogénesis , Glucosa/metabolismo , Hígado/metabolismo , Hipoglucemia/metabolismo , Homeostasis , Lípidos
11.
Cell Mol Neurobiol ; 43(5): 2179-2202, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36266523

RESUMEN

Substantial morbidity and mortality are associated with postcardiac arrest brain injury (PCABI). MicroRNAs(miRNAs) are essential regulators of neuronal metabolism processes and have been shown to contribute to alleviated neurological injury after cardiac arrest. In this study, we identified miRNAs related to the prognosis of patients with neurological dysfunction after cardiopulmonary resuscitation based on data obtained from the Gene Expression Omnibus (GEO) database. Then, we explored the effects of miR-483-5p on mitochondrial biogenesis, mitochondrial-dependent apoptosis, and oxidative stress levels after ischemia‒reperfusion injury in vitro and in vivo. MiR-483-5p was downregulated in PC12 cells and hippocampal samples compared with that in normal group cells and hippocampi. Overexpression of miR-483-5p increased the viability of PC12 cells after ischemia‒reperfusion injury and reduced the proportion of dead cells. A western blot analysis showed that miR-483-5p increased the protein expression of PCG-1, NRF1, and TFAM and reduced the protein expression of Bax and cleaved caspase 3, inhibiting the release of cytochrome c from mitochondria and alleviating oxidative stress injury by inhibiting the production of ROS and reducing MDA activity. We confirmed that miR-483-5p targeted TNFSF8 to regulate the AMPK/JNK pathway, thereby playing a neuroprotective role after cardiopulmonary resuscitation. Hence, this study provides further insights into strategies for inhibiting neurological impairment after cardiopulmonary resuscitation and suggests a potential therapeutic target for PCABI.


Asunto(s)
Paro Cardíaco , MicroARNs , Fármacos Neuroprotectores , Daño por Reperfusión , Ratas , Animales , Humanos , Sistema de Señalización de MAP Quinasas , Fármacos Neuroprotectores/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Apoptosis/genética , Daño por Reperfusión/metabolismo , Mitocondrias/metabolismo , Paro Cardíaco/complicaciones , Paro Cardíaco/genética , Paro Cardíaco/metabolismo
12.
J Biomed Sci ; 30(1): 47, 2023 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-37380972

RESUMEN

BACKGROUND: A large proportion of the patients with cancer do not respond to immunotherapies. Recent studies suggested an important role for tumor-infiltrating cytotoxic T lymphocytes (CTL) in enhancing response to immunotherapy. Here, we aim to identify gene that induce proliferative and cytotoxic states of CD8+ T cells, and to investigate its effect on CAR-T cells against colorectal cancer. METHODS: Correlation between the expression of IFI35 with the activation and cytotoxicity of CD8+ T cells was assessed with TCGA and proteomic databases. Then we constructed murine colon cancer cells over-expressing IFI35 and tested their effect on anti-tumor immunity in both immunodeficient and immunocompetent mouse models. Flow cytometry and immunohistochemistry were performed to assess the immune microenvironment. Western blot analysis was used to identify the potential down-stream signaling pathway regulated by IFI35. We further investigated the efficacy of the rhIFI35 protein in combination with immunotherapeutic treatment. RESULTS: The transcriptional and proteomic analysis of the activation and cytotoxicity of CD8+ T cells in human cancer samples demonstrated that IFI35 expression is correlated with increased CD8+ T cell infiltration and predicted a better outcome in colorectal cancer. The number and cytotoxicity of CD8+ T cells were significantly increased in IFI35-overexpressing tumors. Mechanistically, we identified that the IFNγ-STAT1-IRF7 axis stimulated IFI35 expression, and that IFI35-mediated regulation of CD8+ T cell proliferation and cytotoxicity was dependent on PI3K/AKT/mTOR signaling pathway in vitro. Furthermore, IFI35 protein enhanced the efficacy of CAR-T cells against colorectal cancer cells. CONCLUSION: Our findings identify IFI35 as a new biomarker that can enhance the proliferation and function of CD8+ T cells, as well as increase the efficacy of CAR-T cells against colorectal cancer cells.


Asunto(s)
Antineoplásicos , Neoplasias del Colon , Humanos , Animales , Ratones , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt/genética , Linfocitos T CD8-positivos , Proteómica , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Microambiente Tumoral
13.
Neurochem Res ; 48(10): 3129-3145, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37338793

RESUMEN

Previous studies have shown that AMPK plays an important role in cerebral ischemia-reperfusion injury by participating in apoptosis, but the exact mechanism and target of action remains unclear. This study aimed to investigate the protective mechanism of AMPK activation on brain injury secondary to cardiac arrest. HE, Nills and TUNEL assays were used to evaluate neuronal damage and apoptosis. The relationships between AMPK, HNF4α and apoptotic genes were verified by ChIP-seq, dual-luciferase and WB assays. The results showed that AMPK improved the 7-day memory function of rats, and reduced neuronal cell injury and apoptosis in the hippocampal CA1 region after ROSC, while the use of HNF4α inhibitor weakened the protective effect of AMPK. Further research found that AMPK positively regulated the expression of HNF4α, and AMPK could promote the expression of Bcl-2 and inhibit the expression of Bax and Cleaved-Caspase 3. In vitro experiments showed that AMPK ameliorated neuronal injury by inhibiting apoptosis through the activation of HNF4α. Combined with ChIP-seq, JASPAR analysis and Dual-luciferase assay, the binding site of HNF4α to the upstream promoter of Bcl-2 was found. Taken together, AMPK attenuates brain injury after CA by activating HNF4α to target Bcl-2 to inhibit apoptosis.


Asunto(s)
Lesiones Encefálicas , Paro Cardíaco , Daño por Reperfusión , Ratas , Animales , Ratas Sprague-Dawley , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Paro Cardíaco/complicaciones , Paro Cardíaco/tratamiento farmacológico
14.
BMC Cardiovasc Disord ; 22(1): 573, 2022 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-36581829

RESUMEN

OBJECTIVE: Cardiac arrest (CA) is caused by a nonshockable rhythm with a low success rate of return of spontaneous circulation (ROSC) and a poor prognosis. This study intended to establish a nonshockable rhythm CA model caused by asphyxia. MATERIALS AND METHODS: Healthy adult male Wistar rats were injected with vecuronium bromide to induce CA. After the CA duration reached the target time point, cardiopulmonary resuscitation was performed. The survival status and neurological and cardiac function were evaluated after ROSC. Brain histopathology, including hematoxylin staining, Nissl staining and Terminal dUTP nick-end labeling (TUNEL) staining, was performed to evaluate the surviving cells and apoptotic cells. Apoptosis-related proteins after ROSC for 72 h were analyzed by western blot. RESULTS: CA was successfully induced in all animals. The time for the three groups of animals to PEA was 320 ± 22 s in the CA-8 group, 322 ± 28 s in the CA-12 group and 320 ± 18 s in the CA-15 group. The time to asystole was 436 ± 54 s in the CA-8 group, 438 ± 62 s in the CA-12 group and 433 ± 56 s in the CA-15 group. The NDS of rats in the CA group was significantly decreased after ROSC for 24 h. The NDS in the CA-15 group was 5-16 points, while it was 58-67 points and 15-43 points in the CA-8 and CA-12 groups, respectively. The cardiac function of animals in the CA group was impaired after ROSC, and the ejection fraction, fractional shortening, stroke volume and cardiac output, were all significantly decreased. Brain histopathology showed that the number of surviving neurons was decreased, and the number of apoptotic cells was increased in CA group, the longer the CA duration, the more apoptotic cells increased. The expression of the proapoptotic protein Bax and the apoptotic executive protein caspase3 in the hippocampus of CA rats was significantly increased, while the expression of the antiapoptotic protein Bcl-2 was significantly reduced. CONCLUSIONS: The use of vecuronium can successfully induce CA caused by nonshockable rhythm in rats, which will help to further study the pathophysiological changes after CA by nonshockable rhythm.


Asunto(s)
Reanimación Cardiopulmonar , Paro Cardíaco , Ratas , Masculino , Animales , Asfixia/complicaciones , Ratas Wistar , Paro Cardíaco/etiología , Encéfalo
15.
PLoS Pathog ; 14(11): e1007440, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30462731

RESUMEN

CD4+ T cells play predominant roles in protective immunity against blood-stage Plasmodium infection, both for IFN-γ-dependent effector mechanisms and providing B cell helper signals. Neddylation, an ubiquitination-like process triggered by covalent conjugation of NEDD8 to specific targets, has emerged as a potential regulator of T cell activities to TCR engagement. However, its contribution to T cell-mediated immunity to blood-stage malaria remains unclear. Here using an experimental model induced by Plasmodium yoelii 17XNL, and conditional knockout mice with T cell-specific deficiency of crucial components of neddylation pathway, we demonstrate activation of neddylation in T cells during blood-stage Plasmodium infection is essential for parasite control and host survival. Mechanistically, we show that apart from promoting CD4+ T cell activation, proliferation, and development of protective T helper 1 (Th1) cell response as suggested previously, neddylation is also required for supporting CD4+ T cell survival, mainly through B-cell lymphoma-2 (Bcl-2) mediated suppression of the mitochondria-dependent apoptosis. Furthermore, we provide evidence that neddylation contributes to follicular helper T (Tfh) cell differentiation, probably via augmenting the ubiquitin ligase Itch activity and proteasomal degradation of FoxO1, thereby facilitating germinal center (GC) formation and parasite-specific antibody production. This study identifies neddylation as a positive regulator of anti-Plasmodium immunity and provides insight into an involvement of such pathway in host resistance to infectious diseases.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Malaria/inmunología , Proteína NEDD8/fisiología , Inmunidad Adaptativa/inmunología , Animales , Linfocitos B/inmunología , Inmunidad Celular , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL/fisiología , Ratones Noqueados , Proteína NEDD8/metabolismo , Plasmodium yoelii/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología
16.
Yi Chuan ; 39(7): 607-616, 2017 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-28757475

RESUMEN

Liver cancer and diseases have become the leading cause of deaths in China. Liver diseases including liver failure and liver cancer can be genetic or caused by a variety of factors that damage the liver, such as viruses and alcohol overdose. However, the underlying mechanisms that maintain liver homeostasis remain unclear. Recent studies show that the Hippo signaling pathway plays a critical role in maintaining liver tissue homeostasis. Dysregulation of the Hippo signaling pathway impairs liver regeneration and remarkly enhances liver overgrowth and tumorigenesis. In this review, we summarize recent progresses on the roles and regulation mechanisms of the Hippo signaling pathway in liver development and diseases.


Asunto(s)
Homeostasis , Hígado/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Transducción de Señal/fisiología , Animales , Vía de Señalización Hippo , Humanos , Hígado/embriología , Neoplasias Hepáticas/etiología , Regeneración Hepática
17.
Acta Biochim Biophys Sin (Shanghai) ; 47(1): 46-52, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25476204

RESUMEN

The Hippo signaling pathway is an evolutionarily conserved signaling module that plays critical roles in liver size control and tumorigenesis. The Hippo pathway consists of a core kinase cascade in which the mammalian Ste20-like kinases (Mst1/2, orthologs of Drosophila Hippo) and their cofactor Salvador (Sav1) form a complex to phosphorylate and activate the large tumor suppressor (Lats1/2). Lats1/2 kinases in turn phosphorylate and inhibit the transcription co-activators, the Yes-associated protein (YAP) and the transcriptional co-activator with PDZ-binding motif (TAZ), two major downstream effectors of the Hippo pathway. Losses of the Hippo pathway components induce aberrant hepatomegaly and tumorigenesis, in which YAP coordinates regulation of cell proliferation and apoptosis and plays an essential role. This review summarizes the current findings of the regulation of Hippo signaling in liver regeneration and tumorigenesis, focusing on how the loss of tumor suppressor components of the Hippo pathway results in liver cancers and discussing the molecular mechanisms that regulate the expression and activation of its downstream effector YAP in liver tumorigenesis.


Asunto(s)
Carcinogénesis , Neoplasias Hepáticas/fisiopatología , Regeneración Hepática/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Proteínas de Drosophila/metabolismo , Regulación de la Expresión Génica/fisiología , Vía de Señalización Hippo , Homeostasis/fisiología , Humanos , Neoplasias Hepáticas/patología , Modelos Biológicos , Proteínas Nucleares/metabolismo , Tamaño de los Órganos/fisiología , Transducción de Señal/fisiología , Transactivadores/metabolismo , Activación Transcripcional/fisiología , Proteínas Señalizadoras YAP
18.
Semin Cell Dev Biol ; 23(7): 770-84, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22898666

RESUMEN

The "Hippo" signaling pathway has emerged as a major regulator of cell proliferation and survival in metazoans. The pathway, as delineated by genetic and biochemical studies in Drosophila, consists of a kinase cascade regulated by cell-cell contact and cell polarity that inhibits the transcriptional coactivator Yorkie and its proliferative, anti-differentiation, antiapoptotic transcriptional program. The core pathway components are the GC kinase Hippo, which phosphorylates the noncatalytic polypeptide Mats/Mob1 and, with the assistance of the scaffold protein Salvador, phosphorylates the ndr-family kinase Lats. In turn phospho-Lats, after binding to phospho-Mats, autoactivates and phosphorylates Yorkie, resulting in its nuclear exit. Hippo also uses the scaffold protein Furry and a different Mob protein to control another ndr-like kinase, the morphogenetic regulator Tricornered. Architecturally homologous kinase cascades consisting of a GC kinase, a Mob protein, a scaffolding polypeptide and an ndr-like kinase are well described in yeast; in Saccharomyces cerevisiae, e.g., the MEN pathway promotes mitotic exit whereas the RAM network, using a different GC kinase, Mob protein, scaffold and ndr-like kinase, regulates cell polarity and morphogenesis. In mammals, the Hippo orthologs Mst1 and Mst2 utilize the Salvador ortholog WW45/Sav1 and other scaffolds to regulate the kinases Lats1/Lats2 and ndr1/ndr2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in the epithelial cells of the liver and gut; loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by reduction or elimination of YAP. Despite this conservation, considerable diversification in pathway composition and regulation is already evident; in skin, e.g., YAP phosphorylation is independent of Mst1Mst2 and Lats1Lats2. Moreover, in lymphoid cells, Mst1/Mst2, under the control of the Rap1 GTPase and independent of YAP, promotes integrin clustering, actin remodeling and motility while restraining the proliferation of naïve T cells. This review will summarize current knowledge of the structure and regulation of the kinases Hippo/Mst1&2, their noncatalytic binding partners, Salvador and the Rassf polypeptides, and their major substrates Warts/Lats1&2, Trc/ndr1&2, Mats/Mob1 and FOXO.


Asunto(s)
Proteínas Quinasas/metabolismo , Transducción de Señal , Animales , Activación Enzimática , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mitosis , Especificidad por Sustrato
19.
J Biol Chem ; 288(41): 29680-91, 2013 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-23995842

RESUMEN

Cullin-RING ubiquitin ligases (CRLs) are the largest family of E3 ligases and require cullin neddylation for their activation. The NEDD8-activating enzyme inhibitor MLN4924 reportedly blocked cullin neddylation and inactivated CRLs, which resulted in apoptosis induction and tumor suppression. However, CRL roles in ovarian cancer cell survival and the ovarian tumor repressing effects of MLN4924 are unknown. We show here that CRL4 components are highly expressed in human epithelial ovarian cancer tissues. MLN4924-induced DNA damage, cell cycle arrest, and apoptosis in ovarian cancer cells in a time- and dose-dependent manner. In addition, MLN4924 sensitized ovarian cancer cells to other chemotherapeutic drug treatments. Depletion of CRL4 components Roc1/2, Cul4a, and DDB1 had inhibitory effects on ovarian cancer cells similar to MLN4924 treatment, which suggested that CRL4 inhibition contributed to the chemotherapeutic effect of MLN4924 in ovarian cancers. We also investigated for key CRL4 substrate adaptors required for ovarian cancer cells. Depleting Vprbp/Dcaf1 did not significantly affect ovarian cancer cell growth, even though it was expressed by ovarian cancer tissues. However, depleting Cdt2/Dcaf2 mimicked the pharmacological effects of MLN4924 and caused the accumulation of its substrate, CDT1, both in vitro and in vivo. MLN4924-induced DNA damage and apoptosis were partially rescued by Cdt1 depletion, suggesting that CRL4(CDT2) repression and CDT1 accumulation were key biochemical events contributing to the genotoxic effects of MLN4924 in ovarian cancer cells. Taken together, these results indicate that CRL4(CDT2) is a potential drug target in ovarian cancers and that MLN4924 may be an effective anticancer agent for targeted ovarian cancer therapy.


Asunto(s)
Ciclopentanos/farmacología , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Proteínas Nucleares/genética , Neoplasias Ováricas/tratamiento farmacológico , Pirimidinas/farmacología , Ubiquitina-Proteína Ligasas/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Western Blotting , Carcinoma Epitelial de Ovario , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Daño del ADN , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunohistoquímica , Ratones , Ratones Desnudos , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Proteínas Nucleares/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ubiquitina-Proteína Ligasas/metabolismo
20.
Gastroenterology ; 144(7): 1543-53, 1553.e1, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23454691

RESUMEN

BACKGROUND & AIMS: The Hippo signaling pathway is a context-dependent regulator of cell proliferation, differentiation, and apoptosis in species ranging from Drosophila to humans. In this study, we investigated the role of the core Hippo kinases-Mst1 and Mst2-in pancreatic development and homeostasis. METHODS: We used a Cre/LoxP system to create mice with pancreas-specific disruptions in Mst1 and Mst2 (Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice), the mammalian orthologs of Drosophila Hippo. We used a transgenic approach to overexpress Yap, the downstream mediator of Hippo signaling, in the developing pancreas of mice. RESULTS: Contrary to expectations, the pancreatic mass of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice was reduced compared with wild-type mice, largely because of postnatal de-differentiation of acinar cells into duct-like cells. Development of this phenotype coincided with postnatal reactivation of YAP expression. Ectopic expression of YAP during the secondary transition (a stage at which YAP is normally absent) blocked differentiation of the endocrine and exocrine compartments, whereas loss of a single Yap allele reduced acinar de-differentiation. The phenotype of Pdx1-Cre;Mst1(-/-);Mst2(fl/fl) mice recapitulated cellular and molecular changes observed during chemical-induced pancreatitis in mice. CONCLUSIONS: The mammalian Hippo kinases, and YAP, maintain postnatal pancreatic acinar differentiation in mice.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Páncreas Exocrino/crecimiento & desarrollo , Fosfoproteínas/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas de Ciclo Celular , Diferenciación Celular , Proliferación Celular , Ratones , Ratones Transgénicos , Páncreas Exocrino/fisiología , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas/genética , Serina-Treonina Quinasa 3 , Transducción de Señal , Proteínas Señalizadoras YAP
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