Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Toxicol Lett ; 397: 67-78, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734222

RESUMO

Impairment of the insulin signaling pathway is a key contributor to insulin resistance under arsenic exposure. Specifically, O-GlcNAcylation, an important post-translational modification, plays a crucial role in insulin resistance. Nevertheless, the concrete effect and mechanism of O-GlcNAcylation in arsenic-induced impairment of the insulin signaling pathway remain elusive. Herein, C57BL/6 mice were continuously fed arsenic-containing food, with a total arsenic concentration of 30 mg/kg. We observed that the IRS/Akt/GSK-3ß insulin signaling pathway was impaired, and autophagy was activated in mouse livers and HepG2 cells exposed to arsenic. Additionally, O-GlcNAcylation expression in mouse livers and HepG2 cells was elevated, and the key O-GlcNAcylation homeostasis enzyme, O-GlcNAc transferase (OGT), was upregulated. In vitro, non-targeted metabolomic analysis showed that metabolic disorder was induced, and inhibition of O-GlcNAcylation restored the metabolic profile of HepG2 cells exposed to arsenic. In addition, we found that the compromised insulin signaling pathway was dependent on AMPK activation. Inhibition of AMPK mitigated autophagy activation and impairment of insulin signaling pathway under arsenic exposure. Furthermore, down-regulation of O-GlcNAcylation inhibited AMPK activation, thereby suppressing autophagy activation, and improving the impaired insulin signaling pathway. Collectively, our findings indicate that arsenic can impair the insulin signaling pathway by regulating O-GlcNAcylation homeostasis. Importantly, O-GlcNAcylation inhibition alleviated the impaired insulin signaling pathway by suppressing the AMPK/mTOR-autophagy pathway. This indicates that regulating O-GlcNAcylation may be a potential intervention for the impaired insulin signaling pathway induced by arsenic.


Assuntos
Proteínas Quinases Ativadas por AMP , Arsênio , Autofagia , Regulação para Baixo , Insulina , Camundongos Endogâmicos C57BL , N-Acetilglucosaminiltransferases , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Humanos , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Células Hep G2 , Serina-Treonina Quinases TOR/metabolismo , Insulina/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Regulação para Baixo/efeitos dos fármacos , Arsênio/toxicidade , Masculino , Resistência à Insulina , Camundongos , Fígado/efeitos dos fármacos , Fígado/metabolismo
2.
Cancer Res ; 82(14): 2576-2592, 2022 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-35648393

RESUMO

Recent work has made it clear that pericentriolar material (PCM), the matrix of proteins surrounding centrioles, contributes to most functions of centrosomes. Given the occurrence of centrosome amplification in most solid tumors and the unconventional survival of these tumor cells, it is tempting to hypothesize that gel-like mitotic PCM would cluster extra centrosomes to defend against mitotic errors and increase tumor cell survival. However, because PCM lacks an encompassing membrane, is highly dynamic, and is physically connected to centrioles, few methods can decode the components of this microscale matrix. In this study, we took advantage of differential labeling between two sets of APEX2-centrosome reactions to design a strategy for acquiring the PCM proteome in living undisturbed cells without synchronization treatment, which identified 392 PCM proteins. Localization of ubiquitination promotion proteins away from PCM was a predominant mechanism to maintain the large size of PCM for centrosome clustering during mitosis in cancer cells. Depletion of PCM gene kinesin family member 20A (KIF20A) caused centrosome clustering failure and apoptosis in cancer cells in vitro and in vivo. Thus, our study suggests a strategy for targeting a wide range of tumors exhibiting centrosome amplification and provides a proteomic resource for future mining of PCM proteins. SIGNIFICANCE: This study identifies the proteome of pericentriolar material and reveals therapeutic vulnerabilities in tumors bearing centrosome amplification.


Assuntos
Proteoma , Proteômica , Centríolos/metabolismo , Centrossomo/metabolismo , Humanos , Mitose , Proteoma/metabolismo
3.
Nat Commun ; 13(1): 2663, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35562359

RESUMO

Recent studies have suggested that transcriptional protein condensates (or clusters) may play key roles in gene regulation and cell fate determination. However, it remains largely unclear how the gene regulation function is quantitatively tuned by transcription factor (TF) clustering and whether TF clustering may confer emergent behaviors as in cell fate control systems. Here, to address this, we construct synthetic TFs whose clustering behavior can be chemically controlled. Through single-parameter tuning of the system (i.e., TF clustering propensity), we provide lines of evidence supporting the direct transcriptional activation and amplification of target genes by TF clustering. Single-gene imaging suggests that such amplification results from the modulation of transcriptional dynamics. Importantly, TF clustering propensity modulates the gene regulation function by significantly tuning the effective TF binding affinity and to a lesser extent the ultrasensitivity, contributing to bimodality and sustained response behavior that are reminiscent of canonical cell fate control systems. Collectively, these results demonstrate that TF clustering can modulate the gene regulation function to enable emergent behaviors, and highlight the potential applications of chemically controlled protein clustering.


Assuntos
Regulação da Expressão Gênica , Fatores de Transcrição , Análise por Conglomerados , Fenótipo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional
4.
Mol Cell ; 81(8): 1682-1697.e7, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33651988

RESUMO

The coactivator p300/CREB-binding protein (CBP) regulates genes by facilitating the assembly of transcriptional machinery and by acetylating histones and other factors. However, it remains mostly unclear how both functions of p300 are dynamically coordinated during gene control. Here, we showed that p300 can orchestrate two functions through the formation of dynamic clusters with certain transcription factors (TFs), which is mediated by the interactions between a TF's transactivation domain (TAD) and the intrinsically disordered regions of p300. Co-condensation can enable spatially defined, all-or-none activation of p300's catalytic activity, priming the recruitment of coactivators, including Brd4. We showed that co-condensation can modulate transcriptional initiation rate and burst duration of target genes, underlying nonlinear gene regulatory functions. Such modulation is consistent with how p300 might shape gene bursting kinetics globally. Altogether, these results suggest an intriguing gene regulation mechanism, in which TF and p300 co-condensation contributes to transcriptional bursting regulation and cooperative gene control.


Assuntos
Proteína p300 Associada a E1A/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica/genética , Ativação Transcricional/genética , Acetilação , Animais , Células CHO , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Cricetulus , Regulação da Expressão Gênica/genética , Células HEK293 , Histonas/metabolismo , Humanos , Cinética , Camundongos , Transativadores/metabolismo
5.
Mol Syst Biol ; 16(5): e9335, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32407587

RESUMO

Recent studies have revealed that global extrinsic noise arising from stochasticity in the intracellular biochemical environment plays a critical role in heterogeneous cell physiologies. However, it remains largely unclear how such extrinsic noise dynamically influences downstream reactions and whether it could be neutralized by cellular reactions. Here, using fluorescent protein (FP) maturation as a model biochemical reaction, we explored how cellular reactions might combat global extrinsic noise in mammalian cells. We developed a novel single-cell assay to systematically quantify the maturation rate and the associated noise for over a dozen FPs. By exploiting the variation in the maturation rate for different FPs, we inferred that global extrinsic noise could be temporally filtered by maturation reactions, and as a result, the noise levels for slow-maturing FPs are lower compared to fast-maturing FPs. This mechanism is validated by directly perturbing the maturation rates of specific FPs and measuring the resulting noise levels. Together, our results revealed a potentially general principle governing extrinsic noise propagation, where timescale separation allows cellular reactions to cope with dynamic global extrinsic noise.


Assuntos
Núcleo Celular/metabolismo , Citoplasma/metabolismo , Processos Estocásticos , Animais , Células CHO , Núcleo Celular/genética , Cricetulus , Citoplasma/genética , Expressão Gênica/genética , Processamento de Imagem Assistida por Computador , Cinética , Proteínas Luminescentes/metabolismo , Microscopia de Fluorescência , Análise de Célula Única
6.
EBioMedicine ; 47: 373-383, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31492563

RESUMO

BACKGROUND: The gut microbiota plays important roles in modulating host metabolism. Previous studies have demonstrated differences in the gut microbiome of T2D and prediabetic individuals compared to healthy individuals, with distinct disease-related microbial profiles being reported in groups of different age and ethnicity. However, confounding factors such as anti-diabetic medication hamper identification of the gut microbial changes in disease development. METHOD: We used a combination of in-depth metagenomics and metaproteomics analyses of faecal samples from treatment-naïve type 2 diabetic (TN-T2D, n = 77), pre-diabetic (Pre-DM, n = 80), and normal glucose tolerant (NGT, n = 97) individuals to investigate compositional and functional changes of the gut microbiota and the faecal content of microbial and host proteins in Pre-DM and treatment-naïve T2D individuals to elucidate possible host-microbial interplays characterizing different disease stages. FINDINGS: We observed distinct differences characterizing the gut microbiota of these three groups and validated several key features in an independent TN-T2D cohort. We also demonstrated that the content of several human antimicrobial peptides and pancreatic enzymes differed in faecal samples between three groups. INTERPRETATION: Our findings suggest a complex, disease stage-dependent interplay between the gut microbiota and the host and point to the value of metaproteomics to gain further insight into interplays between the gut microbiota and the host. FUND: The study was supported by the National Natural Science Foundation of China (No. 31601073), the National Key Research and Development Program of China (No. 2017YFC0909703) and the Shenzhen Municipal Government of China (No. JCYJ20170817145809215). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Microbioma Gastrointestinal , Metagenoma , Metagenômica , Proteômica , Cromatografia Líquida , Diabetes Mellitus Tipo 2/terapia , Fezes/virologia , Humanos , Metagenômica/métodos , Proteômica/métodos , Espectrometria de Massas em Tandem
7.
Gigascience ; 6(7): 1-12, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28505362

RESUMO

The relationship between dyslipidemia and type 2 diabetes mellitus (T2D) has been extensively reported, but the global lipid profiles, especially in the East Asia population, associated with the development of T2D remain to be characterized. Liquid chromatography coupled to tandem mass spectrometry was applied to detect the global lipidome in the fasting plasma of 293 Chinese individuals, including 114 T2D patients, 81 prediabetic subjects, and 98 individuals with normal glucose tolerance (NGT). Both qualitative and quantitative analyses revealed a gradual change in plasma lipid features with T2D patients exhibiting characteristics close to those of prediabetic individuals, whereas they differed significantly from individuals with NGT. We constructed and validated a random forest classifier with 28 lipidomic features that effectively discriminated T2D from NGT or prediabetes. Most of the selected features significantly correlated with diabetic clinical indices. Hydroxybutyrylcarnitine was positively correlated with fasting plasma glucose, 2-hour postprandial glucose, glycated hemoglobin, and insulin resistance index (HOMA-IR). Lysophosphatidylcholines such as lysophosphatidylcholine (18:0), lysophosphatidylcholine (18:1), and lysophosphatidylcholine (18:2) were all negatively correlated with HOMA-IR. The altered plasma lipidome in Chinese T2D and prediabetic subjects suggests that lipid features may play a role in the pathogenesis of T2D and that such features may provide a basis for evaluating risk and monitoring disease development.


Assuntos
Diabetes Mellitus Tipo 2/sangue , Lipídeos/sangue , Idoso , Glicemia/metabolismo , China , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...