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1.
Chemistry ; 22(9): 2925-9, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26756283

RESUMO

Using a simple method, the aldehyde groups of zeolitic imidazolate framework-90 (ZIF-90) nanocrystals were converted into carboxyl, amino, and thiol groups, without affecting the integrity of the framework. Notably, for the first time, correlations between functionality and cytotoxicity are also demonstrated via in vitro cytotoxicity assays. The positive charged aminated-ZIF-90 presumably results in either perturbation of cell membrane, more efficient cell uptake, or both. Therefore, the half-maximal effective (EC50 ) concentration of aminated-ZIF-90 has a higher cytotoxicity of about 30 µg mL(-1) .


Assuntos
Imidazóis/química , Nanopartículas/química , Zeolitas/química , Zeolitas/toxicidade , Aldeídos/química , Aminação , Imidazóis/toxicidade , Modelos Moleculares , Compostos de Sulfidrila/química
2.
Cell Rep ; 36(4): 109421, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-34320342

RESUMO

Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.


Assuntos
Diferenciação Celular , Fosfatases de Especificidade Dupla , Megacariócitos , Fosfatases da Proteína Quinase Ativada por Mitógeno , Adulto , Animais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Arginina/metabolismo , Linhagem Celular , Fosfatases de Especificidade Dupla/metabolismo , Estabilidade Enzimática , Células HEK293 , Sistema de Sinalização das MAP Quinases , Megacariócitos/citologia , Megacariócitos/enzimologia , Metilação , Camundongos Endogâmicos C57BL , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Síndromes Mielodisplásicas/enzimologia , Síndromes Mielodisplásicas/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Poliubiquitina/metabolismo , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Proteólise , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Ubiquitinação
3.
Neoplasia ; 22(12): 789-799, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33142243

RESUMO

BRAF inhibitors were approved for the treatment of BRAF-mutant melanoma. However, most patients acquire the resistance to BRAF inhibitors after several months of treatment. miR-524-5p is considered as a tumor suppressor in many cancers, including melanoma. In this study, we investigated the biological functions of miR-524-5p in melanoma with acquired resistance to BRAF inhibitor and evaluated the endogenous miR-524-5p expression as a biomarker for melanoma. The results showed that the expression of miR-524-5p was 0.481-fold lower in melanoma tissues (n = 117) than in nevus tissues (n = 40). Overexpression of miR-524-5p significantly reduced proliferative, anchorage-independent growth, migratory and invasive abilities of BRAF inhibitor-resistant melanoma cells. Moreover, the introduction of miR-524-5p led to a reduced development of BRAF inhibitor-resistant melanoma in vivo. Remarkably, the MAPK/ERK signaling pathway was decreased after treatment with miR-524-5p. Furthermore, next-generation sequencing analysis implied that the complement system, leukocyte extravasation, liver X receptor/retinoid-X-receptor activation, and cAMP-mediated signaling may be related to miR-524-5p-induced pathways in the resistant cells. The miR-524-5p level was higher on average in complete response and long-term partial response patients than in progressive disease and short-term partial response patients treated with BRAF inhibitors. Our results proposed that miR-524-5p could be considered as a target for treatment BRAF inhibitor-resistant melanoma and a prognostic marker in the response of patients to BRAF inhibitors for melanoma.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma , Camundongos , Mutação , Interferência de RNA , Vemurafenib/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Invest Dermatol ; 138(4): 911-921, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29183729

RESUMO

Tumors grow because cancer cells lack the ability to balance cell survival and death signaling pathways. miR-596, a microRNA located at the 8p23.3 locus, has been shown by the TCGA-Assembler to be deleted in a significant number of melanoma samples. Here, we also validated the low levels of miR-596 in melanoma compared to tissue nevi, and Kaplan-Meier curve analysis revealed that low miR-596 expression was associated with worse overall survival. Moreover, we showed that miR-596 overexpression effectively inhibited MAPK/ERK signaling, cell proliferation, migration, and invasion and increased the cell apoptosis of melanoma cells. In addition, we found that miR-596 directly targets MEK1 and two apoptotic proteins, MCL1, and BCL2L1, in melanoma cells. Our findings indicated that miR-596 is an important miRNA that both negatively regulates the MAPK/ERK signaling pathway by targeting MEK1 and modulates the apoptosis pathway by targeting MCL1 and BCL2L1, suggesting that miR-596 could be a therapeutic candidate for treating melanoma, and a prognostic factor for melanoma patients.


Assuntos
DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , MicroRNAs/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Feminino , Humanos , Melanoma/metabolismo , Melanoma/patologia , MicroRNAs/biossíntese , Transdução de Sinais
5.
Blood Adv ; 2(21): 2829-2836, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30373889

RESUMO

Dynamic regulation of histone modification enzymes such as PRMT1 (protein arginine methyltransferase 1) determines the ordered epigenetic transitions in hematopoiesis. Sorting cells according to the expression levels of histone modification enzymes may further define subpopulations in hematopoietic lineages with unique differentiation potentials that are presently defined by surface markers. We discovered a vital near infrared dye, E84, that fluoresces brightly following binding to PRMT1 and excitation with a red laser. The staining intensity as measured by flow cytometry is correlated with the PRMT1 expression level. Importantly, E84 staining has no apparent negative effect on the proliferation of the labeled cells. Given that long-term hematopoietic stem cells (LT-HSCs) produce low levels of PRMT1, we used E84 to sort LT-HSCs from mouse bone marrow. We found that SLAM (the signalling lymphocyte activation molecule family) marker-positive LT-HSCs were enriched in the E84low cell fraction. We then performed bone marrow transplantations with E84high or E84low Lin-Sca1+Kit+ (LSK) cells and showed that whole blood cell lineages were successfully reconstituted 16 weeks after transplanting 200 E84low LSK cells. Thus, E84 is a useful new tool to probe the role of PRMT1 in hematopoiesis and leukemogenesis. Developing E84 and other small molecules to label histone modification enzymes provides a convenient approach without modifying gene loci to study the interaction between hematopoietic stem/progenitor cell epigenetic status and differentiation state.


Assuntos
Células Sanguíneas/metabolismo , Carbocianinas/química , Epigênese Genética , Corantes Fluorescentes/química , Proteína-Arginina N-Metiltransferases/genética , Animais , Ataxina-1/metabolismo , Células Sanguíneas/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Transplante de Medula Óssea , Linhagem da Célula , Citometria de Fluxo/métodos , Células HEK293 , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Antígenos Comuns de Leucócito/metabolismo , Camundongos , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo
6.
Sci Rep ; 6: 32523, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27597445

RESUMO

Cancer stem cells (CSCs), or cancer cells with stem cell-like properties, generally exhibit drug resistance and have highly potent cancer inducing capabilities. Genome-wide expression data collected at public repositories over the last few years provide excellent material for studies that can lead to insights concerning the molecular and functional characteristics of CSCs. Here, we conducted functional genomic studies of CSC based on fourteen PCA-screened high quality public CSC whole genome gene expression datasets and, as control, four high quality non-stem-like cancer cell and non-cancerous stem cell datasets from the Gene Expression Omnibus database. A total of 6,002 molecular signatures were taken from the Molecular Signatures Database and used to characterize the datasets, which, under two-way hierarchical clustering, formed three genotypes. Type 1, consisting of mainly glia CSCs, had significantly enhanced proliferation, and significantly suppressed epithelial-mesenchymal transition (EMT), related functions. Type 2, mainly breast CSCs, had significantly enhanced EMT, but not proliferation, related functions. Type 3, composed of ovarian, prostate, and colon CSCs, had significantly suppressed proliferation related functions and mixed expressions on EMT related functions.


Assuntos
Transição Epitelial-Mesenquimal/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proliferação de Células , Análise por Conglomerados , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Genótipo , Humanos , Análise de Componente Principal
7.
Oncotarget ; 5(19): 9444-59, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25275294

RESUMO

It has been well documented that miRNAs can modulate the effectiveness of cancer-associated signaling pathways. Mitogen-activated protein kinase (MAPK/ERK) signaling plays an essential role in the progression of many cancers, including melanoma and colon cancers. However, no single miRNA is reported to directly target multiple components of the MAPK/ERK pathway. We performed a miRNA PCR array screening with various MAPK/ERK signaling activities. The miRNA array data revealed that the expression of miR-524-5p was decreased in cells with an active MAPK/ERK pathway and confirmed that the expression of miR-524-5p is inversely associated with the activity of the MAPK/ERK pathway. We demonstrated that miR-524-5p directly binds to the 3'-untranslated regions of both BRAFandERK2 and suppresses the expression of these proteins. Because BRAF and ERK2 are the main components of MAPK signaling, the overexpression of miR-524-5p effectively inhibits MAPK/ERK signaling, tumor proliferation, and melanoma cell migration. Moreover, tumors overexpressing miR-524-5p were significantly smaller than those of the negative control mice. Our findings provide new insight into the role of miR-524-5p as an important miRNA that negatively regulates the MAPK/ERK signaling pathway, suggesting that miR-524-5p could be a potent therapeutic candidate for melanoma treatment.


Assuntos
Sistema de Sinalização das MAP Quinases/genética , Melanoma/patologia , MicroRNAs/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Regiões 3' não Traduzidas/genética , Animais , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Masculino , Melanoma/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/biossíntese , Proteína Quinase 1 Ativada por Mitógeno/biossíntese , Proteína Quinase 1 Ativada por Mitógeno/genética , Transplante de Neoplasias , Proteínas Proto-Oncogênicas B-raf/biossíntese , Proteínas Proto-Oncogênicas B-raf/genética , Transplante Heterólogo
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