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1.
Front Mol Neurosci ; 15: 822088, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35600074

RESUMO

Cell pyroptosis is one of the main forms of neuronal injury after cerebral ischemia-reperfusion. It is accompanied by an inflammatory reaction and regulated by the caspase gene family. Electroacupuncture (EA) can reduce neuronal injury caused by cerebral ischemia-reperfusion, and we speculated that EA can prevent neuronal pyroptosis after cerebral ischemia-reperfusion by regulating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/caspase-1 pathway. The cerebral ischemia-reperfusion injury model of C57 and caspase-1 gene knockout (Cas-1 ko) mice was established by Longa's method. EA was conducted at acupoints Chize (LU5), Hegu (LI4), Sanyinjiao (SP6), and Zusanli (ST36) for 1.5 h after cerebral ischemia-reperfusion injury for 20 min, and observation was carried out after 24 h. Neurological deficit scores evaluated the neurological function, cerebral infarction volume was observed by triphenyl tetrazolium chloride (TTC) staining, hematoxylin and eosin (H&E) staining, TUNEL and caspase-1 double-labeled fluorescence staining, and NLRP3 and caspase-1 double-labeled immunofluorescence staining that were used to observe the morphology of neurons in hippocampus, and the protein expression of NLRP3, pro-caspase-1, cleaved caspase-1 p20, pro-interleukin-1ß (IL-1ß), cleaved IL-1ß, and GSDMD was detected by Western blot assay. Results showed that EA could reduce the score of neurological deficit, reduce the volume of cerebral infarction and improve the degree of nerve cell injury, and inhibit NLRP3, pro-caspase-1, cleaved caspase-1 p20, pro-IL-1ß, cleaved IL-1ß, and GSDMD protein expression. In summary, EA plays a neuroprotective role by reducing the pyroptotic neurons that were caspase 1-mediated and inflammatory response after cerebral ischemia-reperfusion.

2.
Cancer Med ; 11(3): 864-879, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34866362

RESUMO

Evidence has been emerging of the importance of long non-coding RNAs (lncRNAs) in genome instability. However, no study has established how to classify such lncRNAs linked to genomic instability, and whether that connection poses a therapeutic significance. Here, we established a computational frame derived from mutator hypothesis by combining profiles of lncRNA expression and those of somatic mutations in a tumor genome, and identified 185 candidate lncRNAs associated with genomic instability in lung adenocarcinoma (LUAD). Through further studies, we established a six lncRNA-based signature, which assigned patients to the high- and low-risk groups with different prognosis. Further validation of this signature was performed in a number of separate cohorts of LUAD patients. In addition, the signature was found closely linked to genomic mutation rates in patients, indicating it could be a useful way to quantify genomic instability. In summary, this research offered a novel method by through which more studies may explore the function of lncRNAs and presented a possible new way for detecting biomarkers associated with genomic instability in cancers.


Assuntos
Adenocarcinoma , RNA Longo não Codificante , Adenocarcinoma/genética , Instabilidade Genômica , Humanos , Pulmão/metabolismo , Prognóstico , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
4.
J Immunol Res ; 2021: 5523832, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337075

RESUMO

Osteosarcoma is a quickly developing, malignant cancer of the bone, which is associated with a bad prognosis. In osteosarcoma, hypoxia promotes the malignant phenotype, which results in a cascade of immunosuppressive processes, poor prognosis, and a high risk of metastasis. Nonetheless, additional methodologies for the study of hyperoxia in the tumor microenvironment also need more analysis. We obtained 88 children patients with osteosarcoma from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and 53 children patients with RNA sequence and clinicopathological data from the Gene Expression Omnibus (GEO). We developed a four-gene signature related to hypoxia to reflect the immune microenvironment in osteosarcoma that predicts survival. A high-risk score indicated a poor prognosis and immunosuppressive microenvironment. The presence of the four-gene signature related to hypoxia was correlated with clinical and molecular features and was an important prognostic predictor for pediatric osteosarcoma patients. In summary, we established and validated a four-gene signature related to hypoxia to forecast recovery and presented an independent prognostic predictor representing overall immune response strength within the osteosarcoma microenvironment.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/mortalidade , Osteossarcoma/mortalidade , Hipóxia Tumoral/genética , Microambiente Tumoral/imunologia , Adolescente , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/terapia , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/terapia , Prognóstico , Transcriptoma/imunologia , Microambiente Tumoral/genética
5.
Curr Top Med Chem ; 21(13): 1113-1120, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34259146

RESUMO

The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. It has been proposed that NCAM polysialylation could be inhibited by two types of heparin inhibitors, low molecular heparin (LMWH) and heparin tetrasaccharide (DP4). This review summarizes how the interactions between Polysialyltransferase Domain (PSTD) in ST8SiaIV and CMP-Sia, and between the PSTD and polySia take place, and how these interactions are inhibited by LMWH and DP4. Our NMR studies indicate that LMWH is a more effective inhibitor than DP4 for inhibition of NCAM polysialylation. The NMR identification of heparin-binding sites in the PSTD may provide insight into the design of specific inhibitors of polysialylation.


Assuntos
Inibidores Enzimáticos/farmacologia , Heparina/farmacologia , Sialiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Heparina/química , Humanos , Domínios Proteicos/efeitos dos fármacos , Sialiltransferases/metabolismo
6.
J Oncol ; 2021: 5550116, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986802

RESUMO

OBJECTIVE: The aim of this research was to create a new genetic signature of immune checkpoint-associated genes as a prognostic method for pediatric acute myeloid leukemia (AML). METHODS: Transcriptome profiles and clinical follow-up details were obtained in Therapeutically Applicable Research to Generate Effective Treatments (TARGET), a database of pediatric tumors. Secondary data was collected from the Gene Expression Omnibus (GEO) to test the observations. In univariate Cox regression and multivariate Cox regression studies, the expression of immune checkpoint-related genes was studied. A three-mRNA signature was developed for predicting pediatric AML patient survival. Furthermore, the GEO cohort was used to confirm the reliability. A bioinformatics method was utilized to identify the diagnostic and prognostic value. RESULTS: A three-gene (STAT1, BATF, EML4) signature was developed to identify patients into two danger categories depending on their OS. A multivariate regression study showed that the immune checkpoint-related signature (STAT1, BATF, EML4) was an independent indicator of pediatric AML. By immune cell subtypes analyses, the signature was correlated with multiple subtypes of immune cells. CONCLUSION: In summary, our three-gene signature can be a useful tool to predict the OS in AML patients.

7.
Exp Cell Res ; 404(1): 112618, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33965401

RESUMO

Androgenetic alopecia (AGA) is the most common type of hair loss dysfunction. Secreted frizzled related protein 1 (SFRP1) is found to be associated with hair loss, but its role in AGA and the regulation mechanism of its transcription level is unclear. The aim of our study is to explore the expression of SFRP1 in AGA samples and its transcriptional mechanism. Male frontal and occipital scalp hair follicles from AGA patients were collected, and human dermal papilla cells (DPCs) were isolated and cultured. SFRP1 gene was cloned and constructed into recombinant plasmids to perform dual-luciferase reporter assay. Transcription factor binding sites were predicted through the Jaspar website and further confirmed by the chromatin immunoprecipitation (ChIP) assay. Expression of genes in DPCs was determined by immunofluorescence (IF) staining, quantitative real-time PCR (qRT-PCR) and western blotting. Our findings showed that SFRP1 was highly expressed in DPCs of AGA patients. The core promoter region of SFRP1 was from -100 to +50 bp and was found to be positively regulated by forkhead box C1 (FOXC1), a transcription factor related to hair growth, both at mRNA and protein level in DPCs. Our study suggests that FOXC1 plays an important role in regulating SFRP1 transcription, which may provide new insights into the development of therapeutic strategies for the treatment of AGA.


Assuntos
Alopecia/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Folículo Piloso/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Alopecia/tratamento farmacológico , Alopecia/genética , Derme/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Fatores de Transcrição/metabolismo
8.
J Cell Mol Med ; 25(10): 4786-4799, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33745232

RESUMO

Sepsis is a systemic inflammatory response syndrome caused by infection, resulting in organ dysfunction. Sepsis-induced acute kidney injury (AKI) is one of the most common potential complications. Increasing reports have shown that M1 and M2 macrophages both take part in the progress of AKI by influencing the level of inflammatory factors and the cell death, including pyroptosis. However, whether M1 and M2 macrophages regulate AKI by secreting exosome remains unknown. In the present study, we isolated the exosomes from M1 and M2 macrophages and used Western blot and enzyme-linked immunosorbent assay (ELISA) to investigate the effect of M1 and M2 exosomes on cell pyroptosis. miRNA sequencing was used to identify the different miRNA in M1 and M2 exosomes. Luciferase reporter assay was used to verify the target gene of miRNA. We confirmed that exosomes excreted by macrophages regulated cell pyroptosis in vitro by using Western blot and ELISA. miRNA sequencing revealed the differentially expressed level of miRNAs in M1 and M2 exosomes, among which miR-93-5p was involved in the regulation of pyroptosis. By using bioinformatics predictions and luciferase reporter assay, we found that thioredoxin-interacting protein (TXNIP) was a direct target of miR-93-5p. Further in vitro and in vivo experiments indicated that exosomal miR-93-5p regulated the TXNIP directly to influence the pyroptosis in renal epithelial cells, which explained the functional difference between different phenotypes of macrophages. This study might provide new targets for the treatment of sepsis-induced AKI.


Assuntos
Injúria Renal Aguda/patologia , Exossomos/patologia , Macrófagos/patologia , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Sepse/complicações , Tiorredoxinas/metabolismo , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Exossomos/genética , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos BALB C , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Tiorredoxinas/genética
9.
J Cell Mol Med ; 24(18): 10478-10492, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32812343

RESUMO

Bronchopulmonary dysplasia (BPD) is a severe complication of preterm infants characterized by increased alveolarization and inflammation. Premature exposure to hyperoxia is believed to be a key contributor to the pathogenesis of BPD. No effective preventive or therapeutic agents have been created. Stimulator of interferon gene (STING) is associated with inflammation and apoptosis in various lung diseases. Long non-coding RNA MALAT1 has been reported to be involved in BPD. However, how MALAT1 regulates STING expression remains unknown. In this study, we assessed that STING and MALAT1 were up-regulated in the lung tissue from BPD neonates, hyperoxia-based rat models and lung epithelial cell lines. Then, using the flow cytometry and cell proliferation assay, we found that down-regulating of STING or MALAT1 inhibited the apoptosis and promoted the proliferation of hyperoxia-treated cells. Subsequently, qRT-PCR, Western blotting and dual-luciferase reporter assays showed that suppressing MALAT1 decreased the expression and promoter activity of STING. Moreover, transcription factor CREB showed its regulatory role in the transcription of STING via a chromatin immunoprecipitation. In conclusion, MALAT1 interacts with CREB to regulate STING transcription in BPD neonates. STING, CREB and MALAT1 may be promising therapeutic targets in the prevention and treatment of BPD.


Assuntos
Displasia Broncopulmonar/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Regulação da Expressão Gênica , Proteínas de Membrana/genética , RNA Longo não Codificante/metabolismo , Transcrição Genética , Animais , Apoptose/genética , Displasia Broncopulmonar/sangue , Linhagem Celular , Proliferação de Células/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Inativação Gênica , Humanos , Hiperóxia/genética , Recém-Nascido , Leucócitos Mononucleares/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Masculino , Proteínas de Membrana/sangue , Modelos Biológicos , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/genética , Ratos , Regulação para Cima/genética
10.
Mol Med Rep ; 22(2): 1639-1646, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32467991

RESUMO

Respiratory syncytial virus (RSV) infection enhances the cell­mediated immune responses of type 2 helper T cells and promotes the progression of allergic inflammation and asthma by producing thymic stromal lymphopoietin (TSLP), especially long isoform TSLP (lfTSLP). However, the role of short isoform TSLP (sfTSLP) in RSV infection remains to be elucidated. The present study was designed to demonstrate the role of both lfTSLP and sfTSLP, as transcription regulators, in RSV infection. The expression of lfTSLP and sfTSLP in RSV­infected Beas­2B cells was analyzed. Activating protein 2 (AP­2)α was overexpressed or knocked down to detect the changes in sfTSLP and lfTSLP expression. Luciferase reporter plasmid and chromatin immunoprecipitation experiments demonstrated that AP­2α bound to the sfTSLP promoter region. LfTSLP and sfTSLP increased while AP­2α decreased in RSV­infected Beas­2B cells. In the Beas­2B cells, AP­2α was found to negatively regulate the activity of the sfTSLP promoter and the mRNA level of sfTSLP. AP­2α also negatively regulated the expression of lfTSLP at both the mRNA and protein levels. The results of the chromatin immunoprecipitation assay indicated that AP­2α bound to the core promoter region of sfTSLP. These results confirmed that the transcription factor AP­2α can repress the expression of lfTSLP and sfTSLP in bronchial epithelial cells in RSV infection.


Assuntos
Citocinas/metabolismo , Infecções por Vírus Respiratório Sincicial/metabolismo , Fator de Transcrição AP-2/metabolismo , Sítios de Ligação , Brônquios/imunologia , Brônquios/metabolismo , Linhagem Celular Transformada , Imunoprecipitação da Cromatina , Biologia Computacional , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Humanos , Luciferases/química , Regiões Promotoras Genéticas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/imunologia , Fator de Transcrição AP-2/imunologia
12.
Int J Mol Sci ; 21(5)2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32111064

RESUMO

Polysialic acid (polySia) is an unusual glycan that posttranslational modifies neural cell adhesion molecule (NCAM) proteins in mammalian cells. The up-regulated expression of polySia-NCAM is associated with tumor progression in many metastatic human cancers and in neurocognitive processes. Two members of the ST8Sia family of α2,8-polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST) both catalyze synthesis of polySia when activated cytidine monophosphate(CMP)-Sialic acid (CMP-Sia) is translocate into the lumen of the Golgi apparatus. Two key polybasic domains in the polySTs, the polybasic region (PBR) and the polysialyltransferase domain (PSTD) areessential forpolysialylation of the NCAM proteins. However, the precise molecular details to describe the interactions required for polysialylation remain unknown. In this study, we hypothesize that PSTD interacts with both CMP-Sia and polySia to catalyze polysialylation of the NCAM proteins. To test this hypothesis, we synthesized a 35-amino acid-PSTD peptide derived from the ST8Sia IV gene sequence and used it to study its interaction with CMP-Sia, and polySia. Our results showed for the PSTD-CMP-Sia interaction,the largest chemical-shift perturbations (CSP) were in amino acid residues V251 to A254 in the short H1 helix, located near the N-terminus of PSTD. However, larger CSP values for the PSTD-polySia interaction were observed in amino acid residues R259 to T270 in the long H2 helix. These differences suggest that CMP-Sia preferentially binds to the domain between the short H1 helix and the longer H2 helix. In contrast, polySia was principally bound to the long H2 helix of PSTD. For the PSTD-polySia interaction, a significant decrease in peak intensity was observed in the 20 amino acid residues located between the N-and C-termini of the long H2 helix in PSTD, suggesting a slower motion in these residues when polySia bound to PSTD. Specific features of the interactions between PSTD-CMP-Sia, and PSTD-polySia were further confirmed by comparing their 800 MHz-derived HSQC spectra with that of PSTD-Sia, PSTD-TriSia (DP 3) and PSTD-polySia. Based on the interactions between PSTD-CMP-Sia, PSTD-polySia, PBR-NCAM and PSTD-PBR, these findingsprovide a greater understanding of the molecular mechanisms underlying polySia-NCAM polysialylation, and thus provides a new perspective for translational pharmacological applications and development by targeting the two polysialyltransferases.


Assuntos
Ácido N-Acetilneuramínico Citidina Monofosfato/metabolismo , Imageamento por Ressonância Magnética/métodos , Moléculas de Adesão de Célula Nervosa/metabolismo , Ácidos Siálicos/metabolismo , Sialiltransferases/química , Sialiltransferases/metabolismo , Complexo de Golgi/metabolismo , Humanos , Modelos Moleculares , Polimerização , Conformação Proteica , Domínios Proteicos
13.
World J Pediatr ; 16(1): 99-110, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31102153

RESUMO

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood driven by aberrant pathways of T-cell activation. T helper 17 (Th17)/regulatory T cell (Treg) imbalance plays critical roles in the pathogenesis of arthritis. MicroRNA-125b (miR-125b) was upregulated after the activation of the initial CD4+ T cells, and could regulate the differentiation of CD4+ T cells. However, the effects of miR-125b on Th17/Treg imbalance and differentiation of Th17/Treg cells remain unknown. METHODS: In this study, we evaluated the expression of miR-125b in the peripheral blood mononuclear cells (PBMCs) of children with JIA, and the relationship of miR-125b with Th17/Treg imbalance. Then, we used lentivirus vector-mediated overexpression technology to investigate the regulatory function of miR-125b in CD4+ T cells or dendritic cell/CD4+ T co-culture system. RESULTS: Decreased miR-125b expression in PBMCs and CD4+ T cells of JIA patients was negatively correlated with the ratio of Th17/Treg cells. It also correlated negatively with retinoic acid receptor-related orphan receptor γt but positively with Forkhead box protein 3 at transcriptional levels. Furthermore, we found that miR-125b overexpression inhibited Th17 cell differentiation, whereas facilitated the differentiation of Treg cells. MiR-125b upregulation led to the decrease of Th17-secreting cytokines but the increase of the Treg-secreting cytokines. CONCLUSIONS: Our results demonstrate that miR-125b participated in regulating Th17/Treg cell differentiation and imbalance in JIA patients. These findings provide novel insight into the critical role of miR-125b in the Th17/Treg imbalance of JIA, and raise the distinct possibility that miR-125b may prove to be a potential therapeutic target for JIA.


Assuntos
Artrite Juvenil/metabolismo , MicroRNAs/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Estudos de Casos e Controles , Diferenciação Celular , Criança , Técnicas de Cocultura , Células Dendríticas/metabolismo , Feminino , Humanos , Masculino , Camundongos
15.
Onco Targets Ther ; 12: 6907-6915, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692554

RESUMO

Purpose: Lung cancer is the most common malignant tumor in the world, and its incidence and mortality are very high. This study focuses on the mechanism of non-small cell lung cancer to find new therapeutic targets. Methods: We used RT-PCR and Western blot to verify the linear relationship between E2F1 and IRF5 in normal lung tissue and lung cancer tissues. Secondly, we used overexpression and knock down E2F1 in cell lines to detect the expression of IRF5. The prime enzyme reporter plasmid verified that E2F1 binds to the core promoter region of IRF5; finally, CHIP experiments demonstrated that E2F1 binds directly to IRF5. Results: We verified that E2F1 and IRF5 are decreased in patient tissues, and there is a strong linear relationship between E2F1 and IRF5. Secondly, we used overexpression of E2F1 or E2F1 siRNA transfected into HCC827 cells and found that E2F1 positively regulates the activity of the IRF5 promoter and the mRNA level of IRF5. Finally, the results of a chromatin immunoprecipitation assay demonstrated that E2F1 bound to the promoter region of IRF5 in vitro. These results suggested that the E2F1 transcription factor is the primary determinant for activating the basal transcription of the IRF5. Conclusion: The transcription factor E2F1 positively regulates IRF5 in non-small cell lung cancer.

16.
Curr Top Med Chem ; 19(31): 2831-2841, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31755393

RESUMO

ST8Sia II (STX) is a highly homologous mammalian polysialyltransferase (polyST), which is a validated tumor-target in the treatment of cancer metastasis reliant on tumor cell polysialylation. PolyST catalyzes the synthesis of α2,8-polysialic acid (polySia) glycans by carrying out the activated CMP-Neu5Ac (Sia) to N- and O-linked oligosaccharide chains on acceptor glycoproteins. In this review article, we summarized the recent studies about intrinsic correlation of two polybasic domains, Polysialyltransferase domain (PSTD) and Polybasic region (PBR) within ST8Sia II molecule, and suggested that the critical amino acid residues within the PSTD and PBR motifs of ST8Sia II for polysialylation of Neural cell adhesion molecules (NCAM) are related to ST8Sia II activity. In addition, the conformational changes of the PSTD domain due to point mutations in the PBR or PSTD domain verified an intramolecular interaction between the PBR and the PSTD. These findings have been incorporated into Zhou's NCAM polysialylation/cell migration model, which will provide new perspectives on drug research and development related to the tumor-target ST8Sia II.


Assuntos
Inibidores Enzimáticos/farmacologia , Sialiltransferases/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Humanos , Mutação Puntual , Domínios Proteicos , Sialiltransferases/genética , Sialiltransferases/metabolismo
17.
Curr Top Med Chem ; 19(25): 2271-2282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648641

RESUMO

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. It has been known that two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research results about the intermolecular interactions between the PBR and NCAM, the PSTD and cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms, which may be helpful to design and develop new polysialyltransferase inhibitors.


Assuntos
Movimento Celular , Moléculas de Adesão de Célula Nervosa/metabolismo , Ácidos Siálicos/metabolismo , Animais , Humanos , Moléculas de Adesão de Célula Nervosa/química , Ácidos Siálicos/química
19.
Cell Signal ; 62: 109355, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276766

RESUMO

Cyclic GMP-AMP synthase (cGAS, cGAMP synthase) plays crucial roles in autoimmune disease, anti-tumor response, anti-senescence and anti-inflammatory response. Many studies have focused on cGAS-mediated signaling pathway. However, transcriptional mechanisms of cGAS gene have remained largely unknown. Here, we cloned the cGAS promoter region and characterized the molecular mechanisms controlling the cGAS transcriptional activity. By a series of 5' deletion and promoter constructions, we showed that the region (-414 to +76 relatives to the transcription start site) was sufficient for promoter activity. Mutation of Sp1 and CREB binding sites in this promoter region led to an apparent reduction of the cGAS promoter activity. Overexpression of Sp1 and CREB could obviously enhance promoter activity, whereas knocking-down of endogenous Sp1 and CREB markedly restrained the cGAS promoter activity. Sp1 and CREB binding to the cGAS promoter region in vivo was verified by Chromatin immunoprecipitation assay. These results pointed out that transcription factors Sp1 and CREB regulate the transcription of the cGAS gene.


Assuntos
Proteína de Ligação a CREB/genética , Nucleotidiltransferases/genética , Fator de Transcrição Sp1/genética , Transcrição Genética , Sítios de Ligação/genética , Imunoprecipitação da Cromatina , Clonagem Molecular , Regulação da Expressão Gênica , Humanos , Nucleotidiltransferases/isolamento & purificação , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Transdução de Sinais/genética , Ativação Transcricional/genética
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