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1.
Front Cell Infect Microbiol ; 14: 1359432, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38779567

RESUMEN

Diabetic nephropathy (DN) is one of the main complications of diabetes and a major cause of end-stage renal disease, which has a severe impact on the quality of life of patients. Strict control of blood sugar and blood pressure, including the use of renin-angiotensin-aldosterone system inhibitors, can delay the progression of diabetic nephropathy but cannot prevent it from eventually developing into end-stage renal disease. In recent years, many studies have shown a close relationship between gut microbiota imbalance and the occurrence and development of DN. This review discusses the latest research findings on the correlation between gut microbiota and microbial metabolites in DN, including the manifestations of the gut microbiota and microbial metabolites in DN patients, the application of the gut microbiota and microbial metabolites in the diagnosis of DN, their role in disease progression, and so on, to elucidate the role of the gut microbiota and microbial metabolites in the occurrence and prevention of DN and provide a theoretical basis and methods for clinical diagnosis and treatment.


Asunto(s)
Nefropatías Diabéticas , Microbioma Gastrointestinal , Humanos , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/microbiología , Progresión de la Enfermedad , Disbiosis
2.
Cell Metab ; 35(12): 2216-2230.e8, 2023 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-37979583

RESUMEN

Mammalian target of rapamycin complex 1 (mTORC1) monitors cellular amino acid changes for function, but the molecular mediators of this process remain to be fully defined. Here, we report that depletion of cellular amino acids, either alone or in combination, leads to the ubiquitination of mTOR, which inhibits mTORC1 kinase activity by preventing substrate recruitment. Mechanistically, amino acid depletion causes accumulation of uncharged tRNAs, thereby stimulating GCN2 to phosphorylate FBXO22, which in turn accrues in the cytoplasm and ubiquitinates mTOR at Lys2066 in a K27-linked manner. Accordingly, mutation of mTOR Lys2066 abolished mTOR ubiquitination in response to amino acid depletion, rendering mTOR insensitive to amino acid starvation both in vitro and in vivo. Collectively, these data reveal a novel mechanism of amino acid sensing by mTORC1 via a previously unknown GCN2-FBXO22-mTOR pathway that is uniquely controlled by uncharged tRNAs.


Asunto(s)
Proteínas Serina-Treonina Quinasas , Serina-Treonina Quinasas TOR , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Aminoácidos/metabolismo , ARN de Transferencia/genética , ARN de Transferencia/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo
3.
Cell Death Dis ; 13(6): 532, 2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35668069

RESUMEN

PTENα and PTENß (PTENα/ß), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/ß proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/ß and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/ß present opposite effects on carcinogenesis from intracellular PTENα/ß, and propose that the tumor-suppressive C-terminal fragment of PTENα/ß might be used as exogenous agent to treat cancer.


Asunto(s)
Furina , Neoplasias Hepáticas , Carcinogénesis , Furina/genética , Humanos , Proproteína Convertasas
4.
Cell Death Differ ; 29(8): 1569-1581, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35140358

RESUMEN

Linker histone H1 proteins contain many variants in mammalian and can stabilize the condensed state of chromatin by binding to nucleosomes and promoting a more inaccessible structure of DNA. However, it is poorly understood how the binding of histone H1s to chromatin DNA is regulated. Screened as one of a collection of epithelial cells-enriched long non-coding RNAs (lncRNAs), here we found that small nucleolar RNA host gene 8 (SNHG8) is a chromatin-localized lncRNA and presents strong interaction and phase separation with histone H1 variants. Moreover, SNHG8 presents stronger ability to bind H1s than linker DNA, and outcompetes linker DNA for H1 binding. Consequently, loss of SNHG8 increases the amount of H1s that bind to chromatin, promotes chromatin condensation, and induces an epithelial differentiation-associated gene expression pattern. Collectively, our results propose that the highly abundant SNHG8 in epithelial cells keeps histone H1 variants out of nucleosome and its loss contributes to epithelial cell differentiation.


Asunto(s)
Histonas , ARN Largo no Codificante , Animales , Cromatina , ADN/metabolismo , Células Epiteliales/metabolismo , Histonas/genética , Histonas/metabolismo , Mamíferos/metabolismo , Nucleosomas , ARN Largo no Codificante/genética
5.
Nat Cell Biol ; 22(1): 135, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31730051

RESUMEN

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

6.
Nat Cell Biol ; 21(11): 1436-1448, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685992

RESUMEN

PTENα and PTENß are two longer translational variants of phosphatase and tensin homolog (PTEN) messenger RNA. Their expressional regulations and functions in carcinogenesis remain largely unknown. Here, we demonstrate that, in contrast with the well-established tumour-suppressive role of canonical PTEN, PTENα and PTENß promote tumourigenesis by directly interacting with the histone H3 lysine 4 (H3K4) presenter WDR5 to promote H3K4 trimethylation and maintain a tumour-promoting signature. We also show that USP9X and FBXW11 bind to the amino-terminal extensions of PTENα/ß, and respectively deubiquitinate and ubiquitinate lysines 235 and 239 in PTENα to regulate PTENα/ß stability. In accordance, USP9X promotes tumourigenesis and FBXW11 suppresses tumourigenesis through PTENα/ß. Taken together, our results indicate that the Pten gene is a double-edged sword for carcinogenesis, and reinterpretation of the importance of the Pten gene in carcinogenesis is warranted.


Asunto(s)
Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Histonas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/genética , Fosfohidrolasa PTEN/genética , Animales , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Desnudos , Fosfohidrolasa PTEN/metabolismo , Proteolisis , Transducción de Señal , Análisis de Supervivencia , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas con Repetición de beta-Transducina/genética , Proteínas con Repetición de beta-Transducina/metabolismo
7.
Nat Commun ; 9(1): 2392, 2018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29921876

RESUMEN

Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers.


Asunto(s)
Empalme Alternativo , Genes Supresores de Tumor , Aparato de Golgi/metabolismo , Fosfohidrolasa PTEN/metabolismo , Precursores del ARN/metabolismo , Animales , Carcinogénesis/genética , Carcinogénesis/metabolismo , Línea Celular , Línea Celular Tumoral , Núcleo Celular/metabolismo , Células Cultivadas , Células HEK293 , Células HeLa , Humanos , Ratones Noqueados , Fosfohidrolasa PTEN/genética , Precursores del ARN/genética , Transducción de Señal , Empalmosomas/genética , Empalmosomas/metabolismo
8.
World J Surg Oncol ; 15(1): 147, 2017 Aug 03.
Artículo en Inglés | MEDLINE | ID: mdl-28774300

RESUMEN

BACKGROUND: Previous studies have revealed the importance of microRNAs' (miRNAs) function as biomarkers in diagnosing human bladder cancer (BC). However, the results are discordant. Consequently, the possibility of miRNAs to be BC biomarkers was summarized in this meta-analysis. METHODS: In this study, the relevant articles were systematically searched from CBM, PubMed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI). The bivariate model was used to calculate the pooled diagnostic parameters and summary receiver operator characteristic (SROC) curve in this meta-analysis, thereby estimating the whole predictive performance. STATA software was used during the whole analysis. RESULTS: Thirty-one studies from 10 articles, including 1556 cases and 1347 controls, were explored in this meta-analysis. In short, the pooled sensitivity, area under the SROC curve, specificity, positive likelihood ratio, diagnostic odds ratio, and negative likelihood ratio were 0.72 (95%CI 0.66-0.76), 0.80 (0.77-0.84), 0.76 (0.71-0.81), 3.0 (2.4-3.8), 8 (5.0-12.0), and 0.37 (0.30-0.46) respectively. Additionally, sub-group and meta-regression analyses revealed that there were significant differences between ethnicity, miRNA profiling, and specimen sub-groups. These results suggested that Asian population-based studies, multiple-miRNA profiling, and blood-based assays might yield a higher diagnostic accuracy than their counterparts. CONCLUSIONS: This meta-analysis demonstrated that miRNAs, particularly multiple miRNAs in the blood, might be novel, useful biomarkers with relatively high sensitivity and specificity and can be used for the diagnosis of BC. However, further prospective studies with more samples should be performed for further validation.


Asunto(s)
Biomarcadores de Tumor/sangre , MicroARNs/sangre , Neoplasias de la Vejiga Urinaria/sangre , Neoplasias de la Vejiga Urinaria/genética , Pueblo Asiatico/genética , Biomarcadores de Tumor/orina , Cistoscopía/efectos adversos , Humanos , Estadificación de Neoplasias , Proteínas Nucleares/orina , Oportunidad Relativa , Curva ROC , Análisis de Regresión , Sensibilidad y Especificidad , Urinálisis/métodos , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/orina
9.
J Neurochem ; 128(6): 798-806, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24188180

RESUMEN

Methyl CpG binding protein 2 (MeCP2) binds to methylated DNA and acts as a transcriptional repressor. Mutations of human MECP2 gene lead to Rett syndrome, a severe neural developmental disorder. Here, we report that the MeCP2 protein can be modified by covalent linkage to small ubiquitin-like modifier (SUMO) and SUMOylation at lysine 223 is necessary for its transcriptional repression function. SUMOylation of MeCP2 is required for the recruitment of histone deacetylase complexes 1/2 complex. Mutation of MeCP2 lysine 223 to arginine abolishes its suppression of gene expression in mouse primary cortical neurons. Significantly, mutation of MeCP2 K223 site leads to developmental deficiency of rat hippocampal synapses in vitro and in vivo. Thus, the SUMOylation of MeCP2 at K223 is a critical switch for transcriptional repression and plays a crucial function in regulating synaptic development in the central nervous system.


Asunto(s)
Hipocampo/fisiología , Proteína 2 de Unión a Metil-CpG/metabolismo , Sumoilación/fisiología , Sinapsis/fisiología , Animales , Animales Recién Nacidos , Femenino , Regulación del Desarrollo de la Expresión Génica , Células HEK293 , Hipocampo/crecimiento & desarrollo , Histona Desacetilasas/metabolismo , Humanos , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Endogámicos C57BL , Neuronas/citología , Neuronas/fisiología , Cultivo Primario de Células , ARN Interferente Pequeño/genética , Ratas , Ratas Sprague-Dawley , Transcripción Genética/fisiología
10.
Sheng Wu Gong Cheng Xue Bao ; 19(5): 566-71, 2003 Sep.
Artículo en Chino | MEDLINE | ID: mdl-15969085

RESUMEN

The Cry1Ab differs most significantly from the other related ICPs by its absence of a carboxyl terminus of 28 amino acids including four cysteines; consequently it is less stable. We report that the helper protein P20 plays a role in the expression and crystallization of Cry1Ab. Three Cry1Ab expression plasmids pT1B, pP1B, and pDP1B, were constructed based on the shuttle vector pHT3101. The vector pT1B does not contain the p20 gene, pP1B carries p20, and pDP1B contains p20 with cry1A(c) promoter. Transformants were obtained by electroporating the plasmids into Bacillus thuringiensis acrystalliferous mutant CryB. Western blot demonstrated that crylAb was expressed as a 130 kD protein in all the transformants, and some of the protein was partially degraded into a 60 kD peptide. Quantitative protein analysis indicated that the amount of the 130 kD protein varied in the transformants and was in the ratio of 1:1.4:1.5 for PT1B, pP1B and pDP1B respectively. For the 60 kD proteins, the ratio was 1:1.1:1.6. Microscopic examination revealed that the size of the typical pyramidal crystals in the three transformants was in the order of T1B < P1B < DP1B. Bioassay showed that T1B, P1B and DP1B were all toxic to the larvae of Helicoverpa armigera with similar LC50. This study suggested that P20 plays a role in the expression and crystallization of Cry1Ab.


Asunto(s)
Bacillus thuringiensis/metabolismo , Proteínas Bacterianas/metabolismo , Bioensayo/métodos , Endotoxinas/metabolismo , Proteínas Hemolisinas/metabolismo , Animales , Bacillus thuringiensis/genética , Bacillus thuringiensis/ultraestructura , Toxinas de Bacillus thuringiensis , Proteínas Bacterianas/genética , Proteínas Bacterianas/farmacología , Western Blotting , Electroporación , Endotoxinas/genética , Endotoxinas/farmacología , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/farmacología , Microscopía Electrónica de Transmisión , Mariposas Nocturnas/efectos de los fármacos , Regiones Promotoras Genéticas/genética
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