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1.
J Cell Physiol ; 2021 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-33393109

RESUMO

Our understanding of signaling pathways regulating the cell fate of human embryonic stem cells (hESCs) is limited. Calcineurin-NFAT signaling is associated with a wide range of biological processes and diseases. However, its role in controlling hESC fate remains unclear. Here, we report that calcineurin A gamma and the NFATc3/SRPX2 axis control the expression of lineage and epithelial-mesenchymal transition (EMT) markers in hESCs. Knockdown of PPP3CC, the gene encoding calcineurin A gamma, or NFATC3, downregulates certain markers both at the self-renewal state and during differentiation of hESCs. Furthermore, NFATc3 interacts with c-JUN and regulates the expression of SRPX2, the gene encoding a secreted glycoprotein known as a ligand of uPAR. We show that SRPX2 is a downstream target of NFATc3. Both SRPX2 and uPAR participate in controlling expression of lineage and EMT markers. Importantly, SRPX2 knockdown diminishes the upregulation of multiple lineage and EMT markers induced by co-overexpression of NFATc3 and c-JUN in hESCs. Together, this study uncovers a previously unknown role of calcineurin A gamma and the NFATc3/SRPX2 axis in modulating the fate determination of hESCs.

2.
J Exp Clin Cancer Res ; 40(1): 38, 2021 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-33485367

RESUMO

BACKGROUND: Radiotherapy resistance is a major obstacle in the treatment of oesophageal squamous cell carcinoma (OSCC). Hypoxia is a critical cause of radioresistance. However, the communication between hypoxic cells and aerobic cells via exosomes during the transfer of radiation resistance remains unclear. METHODS: Exo-miR-340-5p levels were analysed by RNA-seq and qRT-PCR. We co-cultured OSCC cells with isolated normoxic and hypoxic exosomes to study their impact on radiosensitivity. We used a specific exo-miR-340-5p mimic and knock-down retrovirus to explore the role of this miRNA in the transfer of radioresistance from hypoxic to normoxic cells. Dual-luciferase reporter and RIP assays were used to verify KLF10 as a putative target of miR-340-5p. Several in vitro assays were conducted and xenograft models were established to investigate the effect of exo-miR-340-5p on OSCC radiosensitivity. The plasma exo-miR-340-5p levels in OSCC patients were analysed to study the clinical value of this parameter. RESULTS: Hypoxic exosomes alleviated radiation-induced apoptosis and accelerated DNA damage repair. miR-340-5p was highly expressed in hypoxic exosomes and was transferred into normoxic cells, where it induced radioresistance. Overexpression of miR-340-5p in normoxic OSCC cells mimicked the radioresistance of cells co-cultured with hypoxic exosomes. Knockdown of miR-340-5p in hypoxic exosomes reversed the radioresistance effect, indicating that exo-miR-340-5p is critical for hypoxic EV-transferred radioresistance. KLF10 was identified as the direct target of miR-340-5p. Moreover, metformin was found to increase the expression of KLF10 and enhance the radiosensitivity of OSCC. Higher levels of miR-340-5p in the plasma exosomes from OSCC patients are related to a poorer radiotherapy response and prognosis. CONCLUSIONS: Hypoxic tumour cell-derived exosomal miR-340-5p confers radioresistance in OSCC by targeting KLF10/UVRAG, suggesting that miR-340-5p could be a potential biomarker and therapeutic target for the enhancement of radiosensitivity in OSCC. Metformin can increase KLF10 expression, which ameliorates the radioresistance induced by exo-miR-340-5p transfer. Therefore, metformin could be further investigated as a therapeutic option for the treatment of OSCC.

3.
Cancer Lett ; 496: 93-103, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33038490

RESUMO

Oesophageal cancer is associated with high morbidity and mortality rates because it is highly invasive and prone to recurrence and metastasis, with a five-year survival rate of <20%. Therefore, there is an urgent need for new methods aimed at improving therapeutic intervention. Several studies have shown that targeted therapy may be effective for the treatment of oesophageal cancer. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase with kinase activity and scaffolding function, could be overexpressed in a variety of solid tumours, including oesophageal cancer. FAK participates in survival, proliferation, progression, adhesion, invasion, migration, epithelial-to-mesenchymal transition, angiogenesis, DNA damage repair, and other biological processes through multiple signalling pathways in cancer cells. It plays an important role in the occurrence and development of tumours and has been linked to the prognosis of oesophageal cancer. FAK has been suggested as a potential therapeutic target in oesophageal cancer; thus, the combination of FAK inhibitors with chemotherapy, radiotherapy, and immunotherapy is expected to prolong the survival of patients. This paper presents a brief overview of the structure of FAK and its potential role in oesophageal cancer, providing a rationale for the future application of FAK inhibitors in the treatment of the disease.

4.
Gene ; : 145261, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33183740

RESUMO

Radiotherapy is one of the primary therapeutic modalities for patients diagnosed esophageal squamous cell carcinoma(ESCC). Previous studies have shown that chemotherapy resistance could be linked with the overexpression vascular ATPases(V-ATPase) subunits genes. However, it is unknown whether V-ATPase subunits genes play a role in radiotherapy resistance. The aim of this study was to investigate the effect of the ATP6V1C1 in radiotherapy resistance. siRNA and plasmids were used to transfect low expression of ATP6V1C1 in TE13 (human ESCC cell) and high expressed in ECA109 (human ESCC cell), respectively. To observe proliferation, radiosensitivity, apoptosis and DNA-damage response, colony formation assays, EDU assays, flow cytometry and γH2AX assay were used with or without radiation exposure, separately. The quantities of the autophagosomes and autolysosomes by immunofluorescence were calculated. Autophagic microstructure were discovered by transmission electron microscopy, and the study also repeated in vivo by nude mice. Western blot assay was applied to prove changes in relative proteins. We found that suppressing ATP6V1C1 increased the sensitivity of ESCC cells after RT. Silencing ATP6V1C1 with IR suppressed the tumor growth and promoted autophagy. Besides, the underlying mechanism of ATP6V1C1, which is not fatally disrupted, is that ATP6V1C1 with ionizing radiation (IR)decreased apoptosis and inhibited autophagy may by activating mTOR signaling to suppress radiosensitivity for ESCC cells. Thus, we first reported that the ATP6V1C1 may represent a potential radiotherapeutic target by effect on radiation sensitivity for ESCC.

5.
Insect Biochem Mol Biol ; 127: 103491, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33096212

RESUMO

Ecdysteroids are key regulators of embryonic development as well as molting and metamorphosis in insects. Although an active form of ecdysteroids, 20-hydroxyecdysone (20E) is known to be produced through ecdysteroidogenesis from cholesterol and dephosphorylation of 20E-phosphate during embryogenesis in Lepidoptera, the importance of these production mechanisms in embryonic development has been unclear. Here, we investigated the activation timing of ecdysteroidogenesis from cholesterol and 20E-phosphate dephosphorylation during early embryogenesis in non-diapause eggs of the silkmoth Bombyx mori by observing morphological development, quantifying 20E and 20E-phosphate, measuring transcripts of enzymes involved in 20E production, and detecting activity of these enzymes using egg extracts. Stage-dependent 20E fluctuation and changes in mRNA amounts of enzymes suggest that the two 20E-producing mechanisms are activated at different stages during embryogenesis. Furthermore, knockdown of a dephosphorylation enzyme delayed development at early embryogenesis, whereas knockdown of an ecdysteroidogenic enzyme delayed development at early-middle embryogenesis. These results suggest that 20E is primarily produced initially by dephosphorylation of 20E-phosphate, and then by ecdysteroidogenesis from cholesterol to induce progression of embryonic development in B. mori.

6.
Zookeys ; 954: 65-74, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32821205

RESUMO

A new fossil genus and species is described from the Middle Jurassic of China. The type of Sinoelcana minuta gen. et sp. nov. has body and legs preserved. It is distinguished from all other elcanids by the unique combination of wing venation and stout ovipositor. The sickle-shaped ovipositor suggests that the new species had a preference for oviposition on plant material. A world key to the genera of Elcanidae is provided based on the wing venation.

7.
Ann Endocrinol (Paris) ; 81(1): 18-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32127169

RESUMO

BACKGROUND: We aimed to identify key genes and microRNAs (miRNAs) associated with the development of polycystic ovary syndrome (PCOS). METHODS: GSE84376 mRNA microarray data (15 PCOS granulosa cells and 13 control granulosa cells) and GSE34526 mRNA microarray data (7 PCOS granulosa cells and 3 control granulosa cells) were downloaded from the Gene Expression Omnibus (GEO) database. First, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA) for differentially expressed mRNAs, and protein-protein interaction (PPI) network analysis were conducted. Next, miRNA-target genes were analyzed and functions predicted, and a competing endogenous RNA (ceRNA) network was constructed. Finally, the relationship between miR-486-5p and PRELID2 was experimentally validated. RESULTS: Spleen tyrosine kinase (SYK), major histocompatibility complex, class II, DR alpha (HLA-DRA), and interleukin 10 (IL-10) were important nodes in the PPI network. Interestingly, HLA-DRA was significantly enriched in phagosomes mediated by Staphylococcus aureus infection, and in IL-10 enriched during S. aureus infection. One miRNA (miR-486-5p) and a single target gene (PRELID2) were obtained from the ceRNA network. Further experiments showed that miR-486-5p is upregulated and PRELID2 is downregulated in PCOS patient granulosa cells, and that miR-486-5p targets the PRELID2 3'UTR. Topological property analysis showed that hsa-miR-4687-5p downregulation and hsa-miR-4651 upregulation determined the levels of most mRNAs. Levels of the hsa-miR-4651 target gene were significantly enriched in the leukocyte transendothelial migration pathway. CONCLUSIONS: Our results suggest that HLA-DRA and IL-10 may contribute to PCOS progression via phagosome enriched by S. aureus infection, while miR-486-5p may be implicated in follicular development in PCOS by targeting PRELID2. Besides, miR-4651 may be involved in inflammation via leukocyte transendothelial migration, by regulating its target gene. These findings may indicate new directions and constitute a breakthrough in studying the pathophysiology of PCOS.


Assuntos
MicroRNAs/genética , Síndrome do Ovário Policístico/genética , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Células da Granulosa/metabolismo , Humanos , MicroRNAs/metabolismo , Análise em Microsséries , Síndrome do Ovário Policístico/patologia , RNA Mensageiro/metabolismo
9.
Thorac Cancer ; 11(3): 570-580, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31922357

RESUMO

BACKGROUND: Extracellular vesicles (EVs) are endogenous membrane vesicles with a diameter of 30-200 nm. It has been reported that hypoxic cancer cells can release numerous EVs to mediate multiple regional and systemic effects in the tumor microenvironment. METHODS: In this study, we used ultracentrifugation to extract EVs secreted by TE-13, an esophageal squamous carcinoma (ESCC) cell line during normoxia and hypoxia and performed high-throughput sequencing to detect exosomal miRNAs. Gene ontology (GO) and KEGG pathway analyses were used to reveal pathways potentially regulated by the miRNAs. RESULTS: A total of 10 810 miRNAs were detected; 50 were significantly upregulated and 34 were significantly downregulated under hypoxic environment. GO analysis identified enrichment of protein binding, regulation of transcription (DNA-templated), and membrane as molecular function, biological process, and cellular component, respectively. KEGG pathway analysis revealed cancer-associated pathways, phospholipase D signaling pathway, autophagy, focal adhesion and AGE-RAGE signaling as the key pathways. Further verification experiment from qRT-PCR indicated that miR-128-3p, miR-140-3p, miR-340-5p, miR-452-5p, miR-769-5p and miR-1304-p5 were significantly upregulated in EVs from hypoxia TE-13 cells while miR-340-5p was significantly upregulated in two other ESCC cells, ECA109 and TE-1. CONCLUSION: This study, for the first time reveals changes in the expression of exosomal miRNAs in hypoxic ESCC cells and these findings will act as a resource to study the hypoxic tumor microenvironment and ESCC EVs.

10.
J Cell Physiol ; 235(5): 4279-4290, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31612516

RESUMO

Signaling pathways transmit extracellular cues into cells and regulate transcriptome and epigenome to maintain or change the cell identity. Protein kinases and phosphatases are critical for signaling transduction and regulation. Here, we report that CDK11, a member of the CDK family, is required for the maintenance of human embryonic stem cell (hESC) self-renewal. Our results show that, among the three main isoforms of CDK11, CDK11p46 is the main isoform safeguarding the hESC identity. Mechanistically, CDK11 constrains two important mitogen-activated protein kinase (MAPK) signaling pathways (JNK and p38 signaling) through modulating the activity of protein phosphatase 1. Furthermore, CDK11 knockdown activates transforming growth factor ß (TGF-ß)/SMAD2/3 signaling and upregulates certain nonneural differentiation-associated genes. Taken together, this study uncovers a kinase required for hESC self-renewal through fine-tuning MAPK and TGF-ß signaling at appropriate levels. The kinase-phosphatase axis reported here may shed new light on the molecular mechanism sustaining the identity of hESCs.

12.
Zookeys ; 897: 19-28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31857785

RESUMO

A new species of Elcanidae (Orthoptera, Elcanoidea), Parelcana pulchmacula sp. nov., is described based on four new specimens from the Middle Jurassic Jiulongshan Formation of northeastern China. The new species differs from all other known Archelcaninae species by its combination of wing-venation characters. This new finding improves our knowledge of variation on wing venation in elcanid insects and constitutes the first record of Elcanidae from the Daohugou fossil bed (Yanliao Biota) of northeastern China.

13.
Transl Neurosci ; 10: 160-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31637046

RESUMO

Purpose: to study the application of path type early rehabilitation nursing in the nursing of patients with cerebral infarction and to explore its impact on the recovery of neurological function. Methods: Patients with acute cerebral infarction in our hospital were randomly divided into two groups. The control group used conventional treatment methods. The experimental group used path type early rehabilitation care based on conventional treatment methods and observed the curative effect. Results: The NIHSS scores in the experimental group were significantly lower than those in the control group, and the P value was less than 0.05, which was statistically significant. Conclusion: Path type early rehabilitation nursing has a positive effect on the treatment of patients with cerebral infarction, which contributes to the recovery of neurological function of patients and is worthy of promotion in treatment.

14.
Oncol Lett ; 18(2): 2091-2101, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31423282

RESUMO

The response of cancer patients to oxaliplatin combined with 5-fluorouracil (5-FU) is difficult to predict. It has been reported that carcinoma-associated fibroblasts (CAFs) could induce AKT and ERK phosphorylation, and upregulate survivin expression in colorectal cancer (CRC) cells, which could lead to oxaliplatin plus 5-FU resistance. A total of 71 patients with advanced CRC (aCRC) treated with oxaliplatin plus 5-FU were included in the present study. These patients comprised 46 chemotherapy responders and 25 non-responders. The expression levels of α-smooth muscle actin (α-SMA), phosphorylated (p)-AKT, p-ERK and survivin were determined by immunohistochemical evaluation of paraffin-embedded samples from patients. A predictive model was established using a Probabilistic Neural Network model. The high expression of α-SMA, p-AKT and survivin in patients with aCRC were associated with oxaliplatin plus 5-FU resistance (P<0.001, P=0.023 and P=0.001, respectively). Furthermore, patients with stage IV CRC exhibiting high expression levels of α-SMA and survivin experienced a reduced progression-free survival time compared with patients with low expressions of α-SMA and survivin (5.5 vs. 15.0 months; 5.5 vs. 15.0 months; P=0.005 and P=0.001, respectively). Stage IV CRC and high survivin expression predicted a reduced overall survival time compared with that for patients with stage IV CRC and low survivin expression (50.0 vs. 15.0 months; P<0.001). Patients with α-SMA, p-AKT, p-ERK and survivin overexpression were more likely to present with intrinsic resistance to the oxaliplatin plus 5-FU regimen (the accuracies of modeling, validation and prediction were 83.7, 92.9 and 85.7%, respectively). In conclusion, the multifactorial predictive biomarker model of α-SMA, p-AKT, p-ERK and survivin expression for patients with aCRC to predict intrinsic resistance to oxaliplatin plus 5-FU regimens is of great efficiency and accuracy. Patients with high expression of this predictive model may be intrinsically resistant to the oxaliplatin and 5-FU regimen.

15.
Environ Sci Pollut Res Int ; 26(22): 22351-22361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154651

RESUMO

A new method was developed for denitrification and desulfurization using hydrogen peroxide with the aid of an ultrasonic nebulizer to obtain high removal efficiency of NOx and SO2. Comparing with the atomizing nozzles having the aperture size of 0.01~0.02 mm, the droplets generated using the ultrasonic nebulizer show the smallest d50 value of 7.2 µm, with 72% possessing the size less than 10 µm. Based on the numerical simulation of the vaporization rate of droplets, it is indicated that the droplets with the size of 7.2 µm can be vaporized totally at very short residence time (0.11 s) under 130 °C. Effects of influence factors including the reaction temperature, the initial H2O2 concentration, pH value, and the flue gas flow rate were studied on the removal efficiencies of NO and SO2. Using the in-series double-oxidation subsystems with H2O2 concentration of 6 wt%, pH 5.0, and the reaction temperature of 130 °C, the removal efficiencies of SO2 and NO are respectively 100% and 89.3% at the short residence time of 1.8 s, and the removal efficiency of NO can be increased to 100% as the residence time is longer than 3.7 s. It is confirmed that the ultrasonically atomized H2O2 can indeed enhance the removal efficiencies of NO and SO2 at the optimal temperature, owing to the fast vaporization rate of fine droplets as well as the formation of more active radicals to be captured by NO and SO2 simultaneously. The results here provide a promising route to remove effectively the emissions of NO and SO2 simultaneously. Graphical abstract.


Assuntos
Peróxido de Hidrogênio/química , Óxidos de Nitrogênio/química , Dióxido de Enxofre/química , Desnitrificação , Nebulizadores e Vaporizadores , Oxirredução , Temperatura , Ultrassom
16.
J Biol Chem ; 294(25): 9959-9972, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31092598

RESUMO

Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.


Assuntos
Diferenciação Celular , Mesoderma/citologia , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Wnt1/metabolismo , Animais , Células Cultivadas , Mesoderma/metabolismo , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-jun/genética , Ubiquitina-Proteína Ligases/genética , Proteína Wnt1/genética
17.
Stem Cells Dev ; 28(7): 464-476, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717632

RESUMO

Mesenchymal stem cells (MSCs) are important components of the tumor microenvironment, which play an important role in tumor development. Exosomes derived from tumor cells can affect the biological characteristics of MSCs. Our study examined the effects of exosomes derived from gastric cancer cells on MSC immunomodulatory functions. Exosomes were extracted from gastric cancer cell line AGS (AGS-Exos) and cultured with MSCs. MSCs were then cocultured with both human peripheral blood mononuclear cells and macrophages [phorbol-12-myristate-13-acetate (PMA)-stimulated THP1 cells]. The activation levels of T cells and macrophages were detected by flow cytometry and real-time quantitative polymerase chain reaction (RT-PCR). Changes in the MSC signaling pathway after AGS-Exos stimulation were studied using RNA Chip, and the molecular mechanisms of functional change in MSCs were studied by inhibiting the signaling pathway. MSCs treated with AGS-Exos could promote macrophage phagocytosis and upregulate the secretion of proinflammatory factor, and promote the activation of CD69 and CD25 on the surface of T cells. RNA Chip results indicated the abnormal activation of the NF-kB signaling pathway in MSCs after AGS-Exos stimulation, and this was verified by the identification of key proteins in the pathway using western blot analysis. After NF-kB signaling pathway inhibition, the effect of MSCs stimulated by AGS-Exos on T cells and macrophages was markedly weakened. Therefore, AGS-Exos affected the immunomodulation function of MSCs through the NF-kB signaling pathway, which enhanced the ability of MSCs to activate immune cells, maintain the inflammatory environment, and support tumor growth.


Assuntos
Exossomos/imunologia , Imunomodulação , Células-Tronco Mesenquimais/imunologia , NF-kappa B/imunologia , Transdução de Sinais/imunologia , Neoplasias Gástricas/imunologia , Adulto , Animais , Exossomos/patologia , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Nus , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Células THP-1
18.
Biomater Sci ; 7(1): 211-219, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30426113

RESUMO

Development of a photosensitizer that can achieve tumor specificity, improve therapeutic efficacy, and reduce side effects remains a challenge for photodynamic therapy (PDT). In this work, a pH-sensitive activatable nanophotosensitizer (SMSN-ZnPc1) has been elaborately designed, which could be readily prepared by using a functionalized zinc(ii) phthalocyanine (ZnPc) to conjugate with stellate mesoporous silica nanoparticles (SMSNs) through an acid-sensitive hydrazone bond. Meanwhile, a non-activatable analogue SMSN-ZnPc2 has also been prepared as a negative control. The fluorescence emission and singlet oxygen generation of the photosensitizer are essentially quenched in the intact nanophotosensitizer. However, these properties of SMSN-ZnPc1 can be restored greatly both in acidic solutions and at the cellular level. More importantly, after intravenous administration, SMSN-ZnPc1 can also be selectively activated at the tumor site and exhibit efficient tumor growth inhibition in S180 rat ascitic tumor-bearing KM mice with negligible systemic toxicity. It thus may serve as a promising nanoplatform for cancer diagnosis and targeted PDT.


Assuntos
Preparações de Ação Retardada/química , Indóis/uso terapêutico , Nanoconjugados/uso terapêutico , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Compostos Organometálicos/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Dióxido de Silício/química , Animais , Preparações de Ação Retardada/administração & dosagem , Feminino , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Indóis/administração & dosagem , Indóis/química , Camundongos , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Neoplasias/patologia , Imagem Óptica/métodos , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/química , Porosidade , Ratos , Dióxido de Silício/administração & dosagem
19.
Stem Cell Reports ; 11(4): 973-987, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30269953

RESUMO

The protein level of OCT4, a core pluripotency transcription factor, is vital for embryonic stem cell (ESC) maintenance, differentiation, and somatic cell reprogramming. However, how OCT4 protein levels are controlled during reprogramming remains largely unknown. Here, we identify ubiquitin conjugation sites of OCT4 and report that disruption of WWP2-catalyzed OCT4 ubiquitination or ablation of Wwp2 significantly promotes the efficiency of pluripotency induction from mouse embryonic fibroblasts. Mechanistically, disruption of WWP2-mediated OCT4 ubiquitination elevates OCT4 protein stability and H3K4 methylation level during the reprogramming process. Furthermore, we reveal that OCT4 directly activates expression of Ash2l-b, and that ASH2L-B is a major isoform of ASH2L highly expressed in ESCs and required for somatic cell reprogramming. Together, this study emphasizes the importance of ubiquitination manipulation of the reprogramming factor and its interplay with the epigenetic regulator for successful reprogramming, opening a new avenue to improve the efficiency of pluripotency induction.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Lisina/metabolismo , Proteínas Nucleares/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitinação , Sequência de Aminoácidos , Animais , Reprogramação Celular , Embrião de Mamíferos/citologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Fatores de Transcrição Kruppel-Like/metabolismo , Metilação , Camundongos , Mutação/genética , Fator 3 de Transcrição de Octâmero/química , Ligação Proteica , Estabilidade Proteica , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases
20.
Cell Death Dis ; 9(9): 924, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206204

RESUMO

Trophoblast lineages, precursors of the placenta, are essential for post-implantation embryo survival. However, the regulatory network of trophoblast development remains incompletely understood. Here, we report that Cited1, a transcription coactivator, is a robust inducer for trophoblast-like state from mouse embryonic stem cells (ESCs). Depletion of Cited1 in ESCs compromises the trophoblast lineage specification induced by BMP signaling. In contrast, overexpression of Cited1 in ESCs induces a trophoblast-like state with elevated expression of trophoblast marker genes in vitro and generation of trophoblastic tumors in vivo. Furthermore, global transcriptome profile analysis indicates that ectopic Cited1 activates a trophoblast-like transcriptional program in ESCs. Mechanistically, Cited1 interacts with Bmpr2 and Smad4 to activate the Cited1-Bmpr2-Smad1/5/8 axis in the cytoplasm and Cited1-Smad4-p300 complexes in the nucleus, respectively. Collectively, our results show that Cited1 plays an important role in regulating trophoblast lineage specification through activating the BMP signaling pathway.


Assuntos
Proteína Morfogenética Óssea 1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Embrionárias Murinas/citologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Trofoblastos/citologia , Animais , Proteínas Reguladoras de Apoptose , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Linhagem Celular , Proteína p300 Associada a E1A/metabolismo , Feminino , Camundongos , Proteínas Nucleares/genética , Placenta/embriologia , Gravidez , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/genética , Transcrição Genética/genética
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