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1.
J Clin Transl Hepatol ; 12(3): 227-235, 2024 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-38426189

RESUMEN

Background and Aims: Liver iron overload can induce hepatic expression of bone morphogenic protein (BMP) 6 and activate the BMP/SMAD pathway. However, serum iron overload can also activate SMAD but does not induce BMP6 expression. Therefore, the mechanisms through which serum iron overload activates the BMP/SMAD pathway remain unclear. This study aimed to clarify the role of SMURF1 in serum iron overload and the BMP/SMAD pathway. Methods: A cell model of serum iron overload was established by treating hepatocytes with 2 mg/mL of holo-transferrin (Holo-Tf). A serum iron overload mouse model and a liver iron overload mouse model were established by intraperitoneally injecting 10 mg of Holo-Tf into C57BL/6 mice and administering a high-iron diet for 1 week followed by a low-iron diet for 2 days. Western blotting and real-time PCR were performed to evaluate the activation of the BMP/SMAD pathway and the expression of hepcidin. Results: Holo-Tf augmented the sensitivity and responsiveness of hepatocytes to BMP6. The E3 ubiquitin-protein ligase SMURF1 mediated Holo-Tf-induced SMAD1/5 activation and hepcidin expression; specifically, SMURF1 expression dramatically decreased when the serum iron concentration was increased. Additionally, the expression of SMURF1 substrates, which are important molecules involved in the transduction of BMP/SMAD signaling, was significantly upregulated. Furthermore, in vivo analyses confirmed that SMURF1 specifically regulated the BMP/SMAD pathway during serum iron overload. Conclusions: SMURF1 can specifically regulate the BMP/SMAD pathway by augmenting the responsiveness of hepatocytes to BMPs during serum iron overload.

2.
J Nanobiotechnology ; 21(1): 491, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38115054

RESUMEN

Titanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.


Asunto(s)
Antibacterianos , Luz , Antibacterianos/farmacología , Titanio/farmacología
3.
J Cell Mol Med ; 27(23): 3805-3815, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37786319

RESUMEN

Gingival mesenchymal stem cells (GMSCs) are newly developed seed cells for tissue engineering owing to their easy isolation, abundance and high growth rates. Thy-1 is an important regulatory molecule in the differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the function of Thy-1 in the osteogenic differentiation of GMSCs by reducing the expression of Thy-1 using a lentivirus. The results demonstrated that Thy-1 knockdown promoted the osteogenic differentiation of GMSCs in vitro. Validation by RNA-seq revealed an obvious decrease in Vcam1 and Sox9 gene expression with Thy-1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the differentially expressed genes were enriched in the Wnt signalling pathway. We further demonstrated that Thy-1 knockdown promoted osteogenic differentiation of GMSCs by activating the Wnt/ß-catenin signalling pathway. Therefore, Thy-1 has a key regulatory role in the differentiation of GMSCs and maybe a core molecule connecting transcription factors related to the differentiation of MSCs. Our study also highlighted the potential of Thy-1 to modify MSCs, which may help improve their use in tissue engineering.


Asunto(s)
Células Madre Mesenquimatosas , Osteogénesis , Antígenos Thy-1 , beta Catenina/genética , beta Catenina/metabolismo , Diferenciación Celular/genética , Células Cultivadas , Células Madre Mesenquimatosas/metabolismo , Osteogénesis/genética , Vía de Señalización Wnt/genética , Antígenos Thy-1/genética , Antígenos Thy-1/metabolismo
4.
J Oral Pathol Med ; 52(10): 919-929, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37701976

RESUMEN

BACKGROUND: We aimed to establish image recognition and survival prediction models using a novel scoring system of cyclin D1 expression pattern in patients with human papillomavirus-negative oral or oropharyngeal squamous cell carcinoma. METHODS: The clinicopathological data of 610 patients with human papillomavirus-negative oral/oropharyngeal squamous cell carcinoma were analyzed retrospectively. Cox univariate and multivariate risk regression analyses were performed to compare cyclin D1 expression pattern scoring with the traditional scoring method-cyclin D1 expression level scoring-in relation to patients' overall and progression-free survival. An image recognition model employing the cyclin D1 expression pattern scoring system was established by YOLOv5 algorithms. From this model, two independent survival prediction models were established using the DeepHit and DeepSurv algorithms. RESULTS: Cyclin D1 had three expression patterns in oral and oropharyngeal squamous cell carcinoma cancer nests. Superior to cyclin D1 expression level scoring, cyclin D1 expression pattern scoring was significantly correlated with the prognosis of patients with oral squamous cell carcinoma (p < 0.0001) and oropharyngeal squamous cell carcinoma (p < 0.05). Moreover, it was an independent prognostic risk factor in both oral squamous cell carcinoma (p < 0.0001) and oropharyngeal squamous cell carcinoma (p < 0.05). The cyclin D1 expression pattern-derived image recognition model showed an average test set accuracy of 78.48% ± 4.31%. In the overall survival prediction models, the average concordance indices of the test sets established by DeepSurv and DeepHit were 0.71 ± 0.02 and 0.70 ± 0.01, respectively. CONCLUSION: Combined with the image recognition model of the cyclin D1 expression pattern, the survival prediction model had a relatively good prediction effect on the overall survival prognosis of patients with human papillomavirus-negative oral or oropharyngeal squamous cell carcinoma.


Asunto(s)
Carcinoma de Células Escamosas , Aprendizaje Profundo , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas/patología , Ciclina D1/metabolismo , Neoplasias de la Boca/patología , Neoplasias Orofaríngeas/patología , Pronóstico , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello
5.
Science ; 381(6656): eadd6696, 2023 07 28.
Artículo en Inglés | MEDLINE | ID: mdl-37499037

RESUMEN

Aggregation of tau into filamentous inclusions underlies Alzheimer's disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.


Asunto(s)
Agregación Patológica de Proteínas , Tauopatías , Animales , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Neuronas/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo , Tauopatías/genética , Tauopatías/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
7.
Biochem Biophys Res Commun ; 587: 9-15, 2022 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-34861472

RESUMEN

OBJECTIVE: The role of circadian clock in cementogenesis is unclear. This study examines the role of REV-ERBs, one of circadian clock proteins, in proliferation, migration and mineralization of cementoblasts to fill the gap in knowledge. METHODS: Expression pattern of REV-ERBα in cementoblasts was investigated in vivo and in vitro. CCK-8 assay, scratch wound healing assay, alkaline phosphatase (ALP) and alizarin red S (ARS) staining were performed to evaluate the effects of REV-ERBs activation by SR9009 on proliferation, migration and mineralization of OCCM-30, an immortalized cementoblast cell line. Furthermore, mineralization related markers including osterix (OSX), ALP, bone sialoprotein (BSP) and osteocalcin (OCN) were evaluated. RESULTS: Strong expression of REV-ERBα was found in cellular cementum around tooth apex. Rev-erbα mRNA oscillated periodically in OCCM-30 and declined after mineralization induction. REV-ERBs activation by SR9009 inhibited proliferation but promoted migration of OCCM-30 in vitro. Results of ALP and ARS staining suggested that REV-ERBs activation negatively regulated mineralization of OCCM-30. Mechanically, REV-ERBs activation attenuated the expression of OSX and its downstream targets including ALP, BSP and OCN. CONCLUSIONS: REV-ERBs are involved in cementogenesis and negatively regulate mineralization of cementoblasts via inhibiting OSX expression. Our study provides a potential target regarding periodontal and cementum regeneration.


Asunto(s)
Relojes Biológicos/genética , Calcificación Fisiológica/genética , Cemento Dental/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Transformada , Proliferación Celular/efectos de los fármacos , Cementogénesis/efectos de los fármacos , Cementogénesis/genética , Cemento Dental/citología , Cemento Dental/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Humanos , Sialoproteína de Unión a Integrina/genética , Sialoproteína de Unión a Integrina/metabolismo , Ratones , Ratones Endogámicos C57BL , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Pirrolidinas/farmacología , Transducción de Señal , Factor de Transcripción Sp7/genética , Factor de Transcripción Sp7/metabolismo , Tiofenos/farmacología
8.
Nanoscale ; 13(42): 17912-17919, 2021 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-34679146

RESUMEN

Periodontitis is a common chronic inflammatory disease associated with biofilm formation, gingival recession, and supporting bone loss that can lead to the formation of periodontal pockets and, ultimately, tooth loss. Clinical treatment for periodontitis through scaling and antibiotics still faces the problems of unavoidable bleeding, injury to periodontal tissue, drug resistance, and insufficient treatment. Herein we prepared an injectable anti-periodontitis ointment with catalytic activity that consists of Pt nanocluster (PtNC) modified g-C3N4 (CN), and PEG400/PEG4000, which efficiently treated biofilm-infected periodontitis. PtNCs (<2 nm) with ultralow content (0.07%) were formed on the surface of CN using mild ultraviolet (UV) irradiation. Due to the strong O2 adsorption and activation ability of CN-PtNCs and their mutual electron transfer, they show both oxidase-like and peroxidase-like activities and produce reactive oxygen species (ROS) in the dark. CN-PtNCs showed strong biofilm elimination ability towards Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Furthermore, benefiting from the good biocompatibility of CN-PtNCs and the injectable property of the PEG400/PEG4000 ointment, the CN-PtNC ointment with high bioavailability successfully treated periodontitis in rats, alleviating inflammation and reducing bone loss, and showed better performance than periocline. Therefore, this catalytic system is promising for an efficient, non-invasive, and antibiotic-free treatment of periodontitis.


Asunto(s)
Nanopartículas del Metal/uso terapéutico , Periodontitis , Platino (Metal)/uso terapéutico , Animales , Biopelículas/efectos de los fármacos , Catálisis , Escherichia coli , Periodontitis/tratamiento farmacológico , Ratas , Staphylococcus aureus
9.
Nat Cell Biol ; 23(9): 978-991, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34497368

RESUMEN

The extracellular-signal-regulated kinases ERK1 and ERK2 (hereafter ERK1/2) represent the foremost mitogenic pathway in mammalian cells, and their dysregulation drives tumorigenesis and confers therapeutic resistance. ERK1/2 are known to be activated by MAPK/ERK kinase (MEK)-mediated phosphorylation. Here, we show that ERK1/2 are also modified by lysine-63 (K63)-linked polyubiquitin chains. We identify the tripartite motif-containing protein TRIM15 as a ubiquitin ligase and the tumour suppressor CYLD as a deubiquitinase of ERK1/2. TRIM15 and CYLD regulate ERK ubiquitination at defined lysine residues through mutually exclusive interactions as well as opposing activities. K63-linked polyubiquitination enhances ERK interaction with and activation by MEK. Downregulation of TRIM15 inhibits the growth of both drug-responsive and drug-resistant melanomas. Moreover, high TRIM15 expression and low CYLD expression are associated with poor prognosis of patients with melanoma. These findings define a role of K63-linked polyubiquitination in the ERK signalling pathway and suggest a potential target for cancer therapy.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Lisina/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Poliubiquitina/metabolismo , Carcinogénesis/genética , Carcinogénesis/metabolismo , Genes Supresores de Tumor/fisiología , Humanos , Fosforilación/fisiología , Transducción de Señal/fisiología , Ubiquitina/metabolismo
10.
Nature ; 597(7874): 132-137, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34408321

RESUMEN

Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3-10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism.


Asunto(s)
Proteínas Co-Represoras/metabolismo , Chaperonas Moleculares/metabolismo , Pliegue de Proteína , Animales , Línea Celular , Células/metabolismo , Evolución Molecular , Humanos , Modelos Moleculares , Mutación , Agregado de Proteínas , Agregación Patológica de Proteínas/prevención & control , Conformación Proteica , Dominios Proteicos , Desplegamiento Proteico , Deficiencias en la Proteostasis/prevención & control , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
11.
Int J Oral Sci ; 13(1): 14, 2021 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-33846295

RESUMEN

Mineralized tissue regeneration is an important and challenging part of the field of tissue engineering and regeneration. At present, autograft harvest procedures may cause secondary trauma to patients, while bone scaffold materials lack osteogenic activity, resulting in a limited application. Loaded with osteogenic induction growth factor can improve the osteoinductive performance of bone graft, but the explosive release of growth factor may also cause side effects. In this study, we innovatively used platelet-rich fibrin (PRF)-modified bone scaffolds (Bio-Oss®) to replace autograft, and used cytokine (BMP-2) to enhance osteogenesis. Encouragingly, this mixture, which we named "Autograft Mimic (AGM)", has multiple functions and advantages. (1) The fiber network provided by PRF binds the entire bone scaffold together, thereby shaping the bone grafts and maintaining the space of the defect area. (2) The sustained release of BMP-2 from bone graft promoted bone regeneration continuously. (3) AGM recruited bone marrow mesenchymal stem cells (BMSCs) and promote their proliferation, migration, and osteogenic differentiation. Thus, AGM developed in this study can improve osteogenesis, and provide new guidance for the development of clinical bone grafts.


Asunto(s)
Células Madre Mesenquimatosas , Osteogénesis , Autoinjertos , Regeneración Ósea , Diferenciación Celular , Humanos , Ingeniería de Tejidos , Andamios del Tejido
12.
Cell Rep ; 33(9): 108418, 2020 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-33264628

RESUMEN

Neurodegenerative diseases are characterized by the formation and propagation of protein aggregates, especially amyloid fibrils. However, what normally suppresses protein misfolding and aggregation in metazoan cells remains incompletely understood. Here, we show that TRIM11, a member of the metazoan tripartite motif (TRIM) family, both prevents the formation of protein aggregates and dissolves pre-existing protein deposits, including amyloid fibrils. These molecular chaperone and disaggregase activities are ATP independent. They enhance folding and solubility of normal proteins and cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and restores viability in cell models of Parkinson's disease (PD). Intracranial adeno-associated viral delivery of TRIM11 mitigates α-synuclein-mediated pathology, neurodegeneration, and motor impairments in a PD mouse model. Other TRIMs can also function as ATP-independent molecular chaperones and disaggregases. Thus, we define TRIMs as a potent and multifunctional protein quality-control system in metazoa, which might be applied to treat neurodegenerative diseases.


Asunto(s)
Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Enfermedad de Parkinson/patología , Agregado de Proteínas
13.
Biochem Biophys Res Commun ; 505(1): 325-332, 2018 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-30249398

RESUMEN

Spindlin1 (SPIN1), a histone modification reader protein, was enriched in the cell nucleolus and facilitated rRNA expression. However, how SPIN1 localizes to the nucleolus and its functional role in rRNA gene expression remain unresolved. Here, we identified a nucleolar localization signal in the N-terminal region of SPIN1 that is essential for its enrichment and function in the nucleolus. We also discovered that, in addition to its H3K4me3 recognizing activity, the H3R8me2a-recognizing capacity of SPIN1 is also indispensable for stimulating rRNA expression. Chromatin immunoprecipitation results indicated that SPIN1 is required for the association or assembly of selective factor 1 (SL1) complex, probably facilitating the initiation of rDNA transcription through its H3 K4me3-R8me2a reader function.


Asunto(s)
Proteínas de Ciclo Celular/genética , Nucléolo Celular/genética , Expresión Génica , Genes de ARNr/genética , Histonas/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Fosfoproteínas/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Nucléolo Celular/metabolismo , Inmunoprecipitación de Cromatina , Células HEK293 , Células HeLa , Humanos , Metilación , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Proteínas del Complejo de Iniciación de Transcripción Pol1/genética , Proteínas del Complejo de Iniciación de Transcripción Pol1/metabolismo , Unión Proteica , Interferencia de ARN , Transducción de Señal/genética
14.
Nat Commun ; 9(1): 1223, 2018 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-29581427

RESUMEN

The proteasome is a complex protease critical for protein quality control and cell regulation, and its dysfunction is associated with cancer and other diseases. However, the mechanisms that control proteasome activity  in normal and malignant cells remain unclear. Here we report that TRIM11 enhances degradation of aberrant and normal regulatory proteins, and augments overall rate of proteolysis. Mechanistically, TRIM11 binds to both the proteasome and USP14, a deubiquitinase that prematurely removes ubiquitins from proteasome-bound substrates and also noncatalytically inhibits the proteasome, and precludes their association, thereby increasing proteasome activity. TRIM11 promotes cell survival and is upregulated upon heat shock. Moreover, TRIM11 is required for tumor growth, and increased expression of TRIM11 correlates with poor clinical survival. These findings identify TRIM11 as an important activator of the proteasome, define a pathway that adjusts proteasome activity, and reveal a mechanism by which tumor cells acquire higher degradative power to support oncogenic growth.


Asunto(s)
Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas de Motivos Tripartitos/fisiología , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina-Proteína Ligasas/fisiología , Animales , Carcinogénesis , Línea Celular , Línea Celular Tumoral , Proliferación Celular/fisiología , Supervivencia Celular/fisiología , Células Cultivadas , Enzimas Desubicuitinizantes/metabolismo , Activación Enzimática , Homeostasis , Humanos , Ratones , Unión Proteica , Conformación Proteica , Pliegue de Proteína , Proteolisis , Proteínas de Motivos Tripartitos/química , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/química , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/metabolismo , Regulación hacia Arriba
15.
Opt Express ; 26(24): 31391-31401, 2018 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-30650725

RESUMEN

Simultaneously obtaining high photon emission rate and collection efficiency is highly desirable for applications of single photon sources. However, it remains great challenging and is seldom reported before. Here, we demonstrate that highly enhanced radiation of the emitter and efficient collection of the emitted photons can be simultaneously fulfilled in a hybrid photonic-plasmonic cavity which comprises of an Au nanorod dimer and a photonic crystal nanobeam cavity with a collecting waveguide, where the resonance wavelength of nanobeam cavity is red-detuned from that of the Au nanorod dimer. Our calculations show that the spontaneous emission rate of a single emitter can be enhanced by 5060 -folds, correspondingly, the far-field radiation efficiency and collection efficiency into a dielectric waveguide reaches ~97% and ~67%, respectively. The proposed mechanism paves the way towards the practical applications in ultra-bright on-chip single photon sources and plasmon-based nanolasers.

16.
J Cell Sci ; 127(Pt 22): 4833-45, 2014 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-25236602

RESUMEN

Wnt-ß-catenin (ß-catenin is also known as CTNNB1 in human) signaling through the ß-catenin-TCF complex plays crucial roles in tissue homeostasis. Wnt-stimulated ß-catenin-TCF complex accumulation in the nucleus regulates cell survival, proliferation and differentiation through the transcription of target genes. Compared with their levels in G1, activation of the receptor LRP6 and cytosolic ß-catenin are both upregulated in G2 cells. However, accumulation of the Wnt pathway negative regulator AXIN2 also occurs in this phase. Therefore, it is unclear whether Wnt signaling is active in G2 phase cells. Here, we established a bimolecular fluorescence complementation (BiFC) biosensor system for the direct visualization of the ß-catenin-TCF interaction in living cells. Using the BiFC biosensor and co-immunoprecipitation experiments, we demonstrate that levels of the nucleus-localized ß-catenin-TCF complex increase during the S and G2 phases, and declines in the next G1 phase. Accordingly, a subset of Wnt target genes is transcribed by the ß-catenin-TCF complex during both the S and G2 phases. By contrast, transient inhibition of this complex disturbs both cell survival and G2/M progression. Our results suggest that in S and G2 phase cells, Wnt-ß-catenin signaling is highly active and functions to ensure cell survival and cell cycle progression.


Asunto(s)
Fase G2/fisiología , Fase S/fisiología , beta Catenina/metabolismo , Línea Celular Tumoral , Núcleo Celular/metabolismo , Supervivencia Celular/fisiología , Expresión Génica , Células HeLa , Humanos , Transducción de Señal , Transcripción Genética , Activación Transcripcional , beta Catenina/genética
17.
J Biol Chem ; 289(22): 15482-94, 2014 May 30.
Artículo en Inglés | MEDLINE | ID: mdl-24737324

RESUMEN

The Rac1/JNK cascade plays important roles in DNA damage-induced apoptosis. However, how this cascade is activated upon DNA damage remains to be fully understood. We show here that, in untreated cells, Tiam1, a Rac1-specific guanine nucleotide exchange factor, is phosphorylated by casein kinase 1 (CK1) at its C terminus, leading to Skp, Cullin, F-box-containing(ß-TrCP) recognition, ubiquitination, and proteasome-mediated degradation. Upon DNA-damaging anticancer drug treatment, CK1/ß-TrCP-mediated Tiam1 degradation is abolished, and the accumulated Tiam1 contributes to downstream activation of Rac1/JNK. Consistently, tumor cells overexpressing Tiam1 are hypersensitive to DNA-damaging drug treatment. In xenograft mice, Tiam1-high cells are more susceptible to doxorubicin treatment. Thus, our results uncover that inhibition of proteasome-mediated Tiam1 degradation is an upstream event leading to Rac1/JNK activation and cell apoptosis in response to DNA-damaging drug treatment.


Asunto(s)
Apoptosis/fisiología , Daño del ADN/fisiología , Factores de Intercambio de Guanina Nucleótido/metabolismo , Transducción de Señal/fisiología , Neoplasias del Cuello Uterino , Proteínas con Repetición de beta-Transducina/metabolismo , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/genética , Quinasa de la Caseína I/metabolismo , Daño del ADN/efectos de los fármacos , Doxorrubicina/toxicidad , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Células HEK293 , Células HeLa , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Ratones Desnudos , Transducción de Señal/genética , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación/fisiología , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas con Repetición de beta-Transducina/genética , Proteína de Unión al GTP rac1/metabolismo
18.
Genes Dev ; 28(6): 622-36, 2014 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-24589551

RESUMEN

Histone modification patterns and their combinatorial readout have emerged as a fundamental mechanism for epigenetic regulation. Here we characterized Spindlin1 as a histone effector that senses a cis-tail histone H3 methylation pattern involving trimethyllysine 4 (H3K4me3) and asymmetric dimethylarginine 8 (H3R8me2a) marks. Spindlin1 consists of triple tudor-like Spin/Ssty repeats. Cocrystal structure determination established concurrent recognition of H3K4me3 and H3R8me2a by Spin/Ssty repeats 2 and 1, respectively. Both H3K4me3 and H3R8me2a are recognized using an "insertion cavity" recognition mode, contributing to a methylation state-specific layer of regulation. In vivo functional studies suggest that Spindlin1 activates Wnt/ß-catenin signaling downstream from protein arginine methyltransferase 2 (PRMT2) and the MLL complex, which together are capable of generating a specific H3 "K4me3-R8me2a" pattern. Mutagenesis of Spindlin1 reader pockets impairs activation of Wnt target genes. Taken together, our work connects a histone "lysine-arginine" methylation pattern readout by Spindlin1-to-Wnt signaling at the transcriptional level.


Asunto(s)
Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/metabolismo , Histonas/química , Histonas/metabolismo , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Fosfoproteínas/química , Fosfoproteínas/metabolismo , Transducción de Señal , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Proteínas de Ciclo Celular/genética , Células HCT116 , Células HEK293 , Humanos , Metilación , Repeticiones de Microsatélite , Proteínas Asociadas a Microtúbulos/genética , Mutagénesis , Fosfoproteínas/genética , Estructura Terciaria de Proteína , Factor de Transcripción 4 , Factores de Transcripción/metabolismo , Proteínas Wnt/metabolismo
20.
J Biol Chem ; 285(14): 10890-901, 2010 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-20103590

RESUMEN

The beta-catenin-lymphoid enhancer factor (LEF) protein complex is the key mediator of canonical Wnt signaling and initiates target gene transcription upon ligand stimulation. In addition to beta-catenin and LEF themselves, many other proteins have been identified as necessary cofactors. Here we report that the evolutionally conserved splicing factor and transcriptional co-regulator, SKIP/SNW/NcoA62, forms a ternary complex with LEF1 and HDAC1 and mediates the repression of target genes. Loss-of-function studies showed that SKIP is obligatory for Wnt signaling-induced target gene transactivation, suggesting an important role of SKIP in the canonical Wnt signaling. Consistent with its involvement in beta-catenin signaling, the C-terminally truncated forms of SKIP are able to stabilize beta-catenin and enhance Wnt signaling. In Xenopus embryos, both overexpression and knockdown of Skip lead to reduced neural crest induction, consistent with down-regulated Wnt signaling in both cases. Our results indicate that SKIP is a novel component of the beta-catenin transcriptional complex.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Regulación del Desarrollo de la Expresión Génica , Cresta Neural/metabolismo , Transducción de Señal , Proteína Wnt1/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Western Blotting , Inmunoprecipitación de Cromatina , Embrión no Mamífero/citología , Embrión no Mamífero/metabolismo , Biblioteca de Genes , Células HeLa , Humanos , Técnicas para Inmunoenzimas , Luciferasas/metabolismo , Ratones , Cresta Neural/citología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Wnt1/genética , Xenopus laevis , beta Catenina/genética
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