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  1 / 905 MEDLINE  
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[PMID]:28631560
[Au] Autor:Li J; Gao H; Meng L; Yin L
[Ad] Endereço:Department of Stomatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
[Ti] Título:Mithramycin inhibits epithelial-to-mesenchymal transition and invasion by downregulating SP1 and SNAI1 in salivary adenoid cystic carcinoma.
[So] Source:Tumour Biol;39(6):1010428317708697, 2017 Jun.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mithramycin exhibits certain anticancer effects in glioma, metastatic cerebral carcinoma, malignant lymphoma, chorionic carcinoma and breast cancer. However, its effects on salivary adenoid cystic carcinoma remain unclear. Here, we report that mithramycin significantly inhibited epithelial-to-mesenchymal transition and invasion in human salivary adenoid cystic carcinoma cell lines. The underlying mechanism for this activity was further demonstrated to involve decreasing the expression of the transcription factors specificity protein 1 and SNAI1. Specificity protein 1 is a pro-tumourigenic transcription factor that is overexpressed in SACC-LM and SACC-83 cells, and its expression is inhibited by mithramycin. Moreover, chromatin immunoprecipitation assays showed that specificity protein 1 induced SNAI1 transcription through direct binding to the SNAI1 promoter. In summary, this study uncovered the mechanism through which mithramycin inhibits epithelial-to-mesenchymal transition and invasion in salivary adenoid cystic carcinoma cell lines, namely, via downregulating specificity protein 1 and SNAI1 expression, which suggests mithramycin may be a promising therapeutic option for salivary adenoid cystic carcinoma.
[Mh] Termos MeSH primário: Carcinoma Adenoide Cístico/tratamento farmacológico
Plicamicina/administração & dosagem
Fatores de Transcrição da Família Snail/genética
Fator de Transcrição Sp1/genética
[Mh] Termos MeSH secundário: Carcinoma Adenoide Cístico/genética
Carcinoma Adenoide Cístico/patologia
Linhagem Celular Tumoral
Movimento Celular/efeitos dos fármacos
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Regiões Promotoras Genéticas/genética
Fatores de Transcrição da Família Snail/metabolismo
Fator de Transcrição Sp1/metabolismo
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (SNAI1 protein, human); 0 (Snail Family Transcription Factors); 0 (Sp1 Transcription Factor); 0 (Sp1 protein, human); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317708697


  2 / 905 MEDLINE  
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[PMID]:28322791
[Au] Autor:Alamuru-Yellapragada NP; Vundyala S; Behera S; Parsa KV
[Ad] Endereço:Department of Biology, Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Hyderabad, Telangana, India.
[Ti] Título:LPS depletes PHLPP levels in macrophages through the inhibition of SP1 dependent transcriptional regulation.
[So] Source:Biochem Biophys Res Commun;486(2):533-538, 2017 Apr 29.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We have previously reported that bacterial endotoxin LPS attenuates expression of PHLPP, a ser/thr phosphatase, at both transcript and protein levels in different immune cells, however the underlying molecular mechanism is unknown and is of significant interest. Here, in line with the decreased transcript levels upon LPS treatment, we observed that LPS caused significant reduction in PHLPP promoter activity. We observed that SP1, a transcription factor frequently associated with inflammation, was recruited to the PHLPP promoter region. Ectopic expression of SP1 enhanced both transcript and protein levels of PHLPP while knockdown of SP1 or pharmacological inhibition of SP1 DNA binding by mithramycin reduced PHLPP expression. Moreover, over-expression of SP1 co-activators CBP/p300 augmented SP1 driven PHLPP promoter activity. Of note, LPS treatment depleted SP1 and CBP protein levels due to which recruitment of SP1 to PHLPP promoter was reduced. Further, we found that re-introduction of SP1 restored promoter activity and transcript levels of PHLPP in LPS stimulated cells. Collectively, our data revealed the molecular mechanism underlying the regulation of PHLPP expression during LPS induced macrophage inflammatory response.
[Mh] Termos MeSH primário: Lipopolissacarídeos/farmacologia
Macrófagos/efeitos dos fármacos
Proteínas Nucleares/genética
Fosfoproteínas Fosfatases/genética
RNA Mensageiro/genética
Fator de Transcrição Sp1/genética
[Mh] Termos MeSH secundário: Animais
Linhagem Celular
Regulação da Expressão Gênica
Genes Reporter
Células HEK293
Seres Humanos
Luciferases/genética
Luciferases/metabolismo
Macrófagos/citologia
Macrófagos/imunologia
Camundongos
Monócitos/citologia
Monócitos/efeitos dos fármacos
Monócitos/imunologia
Proteínas Nucleares/antagonistas & inibidores
Proteínas Nucleares/imunologia
Fosfoproteínas Fosfatases/antagonistas & inibidores
Fosfoproteínas Fosfatases/imunologia
Plicamicina/farmacologia
Regiões Promotoras Genéticas
RNA Mensageiro/imunologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Transdução de Sinais
Fator de Transcrição Sp1/imunologia
Transcrição Genética
Fatores de Transcrição de p300-CBP/genética
Fatores de Transcrição de p300-CBP/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipopolysaccharides); 0 (Nuclear Proteins); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Sp1 Transcription Factor); 0 (Sp1 protein, human); EC 1.13.12.- (Luciferases); EC 2.3.1.48 (p300-CBP Transcription Factors); EC 3.1.3.16 (PHLPP1 protein, human); EC 3.1.3.16 (Phosphoprotein Phosphatases); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE


  3 / 905 MEDLINE  
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[PMID]:27924419
[Au] Autor:Carvalho JL; Britto A; de Oliveira AP; Castro-Faria-Neto H; Albertini R; Anatriello E; Aimbire F
[Ad] Endereço:Department of Science and Technology, Federal University of São Paulo - UNIFESP, São José dos Campos, SP, Brazil.
[Ti] Título:Beneficial effect of low-level laser therapy in acute lung injury after i-I/R is dependent on the secretion of IL-10 and independent of the TLR/MyD88 signaling.
[So] Source:Lasers Med Sci;32(2):305-315, 2017 Feb.
[Is] ISSN:1435-604X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The use of low-level laser for lung inflammation treatment has been evidenced in animal studies as well as clinical trials. The laser action mechanism seems to involve downregulation of neutrophil chemoattractants and transcription factors. Innate immune responses against microorganisms may be mediated by toll-like receptors (TLR). Intestinal ischemia and reperfusion (i-I/R) lead to bacterial product translocation, such as endotoxin, which consequently activates TLRs leading to intestinal and lung inflammation after gut trauma. Thus, the target of this study was to investigate the role of TLR activation in the laser (660 nm, 30 mW, 67.5 J/cm , 0.375 mW/cm , 5.4 J, 180 s, and spot size with 0.08 cm ) effect applied in contact with the skin on axillary lymph node in lung inflammation induced by i-I/R through a signaling adaptor protein known as myeloid differentiation factor 88 (MyD88). It is a quantitative, experimental, and laboratory research using the C57Bl/6 and MyD88 mice (n = 6 mice for experimental group). Statistical differences were evaluated by ANOVA and the Tukey-Kramer multiple comparisons test to determine differences among groups. In order to understand how the absence of MyD88 can interfere in the laser effect on lung inflammation, MyD88 mice were treated or not with laser and subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). In summary, the laser decreased the MPO activity and the lung vascular permeability, thickened the alveolar septa, reduced both the edema and the alveolar hemorrhage, as well as significantly decreased neutrophils infiltration in MyD88-deficient mice as well in wild-type mice. It noted a downregulation in chemokine IL-8 production as well as a cytokine IL-10 upregulation in these animals. The results also evidenced that in absence of IL-10, the laser effect is reversed. Based on these results, we suggest that the beneficial effect of laser in acute lung injury after i-I/R is dependent on the secretion of IL-10 and independent of the TLR/MyD88 signaling.
[Mh] Termos MeSH primário: Lesão Pulmonar Aguda/radioterapia
Interleucina-10/secreção
Intestinos/irrigação sanguínea
Terapia com Luz de Baixa Intensidade/métodos
Fator 88 de Diferenciação Mieloide/metabolismo
Traumatismo por Reperfusão/patologia
Transdução de Sinais
Receptores Toll-Like/metabolismo
[Mh] Termos MeSH secundário: Lesão Pulmonar Aguda/complicações
Lesão Pulmonar Aguda/genética
Animais
Regulação da Expressão Gênica/efeitos dos fármacos
Inflamação/metabolismo
Molécula 1 de Adesão Intercelular/metabolismo
Interleucina-10/genética
Interleucina-8/genética
Interleucina-8/metabolismo
Intestinos/patologia
Pulmão/irrigação sanguínea
Pulmão/metabolismo
Pulmão/patologia
Camundongos Endogâmicos C57BL
Microvasos/efeitos dos fármacos
Microvasos/patologia
Peroxidase/metabolismo
Plicamicina/farmacologia
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Traumatismo por Reperfusão/complicações
Traumatismo por Reperfusão/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-8); 0 (Myeloid Differentiation Factor 88); 0 (RNA, Messenger); 0 (Toll-Like Receptors); 126547-89-5 (Intercellular Adhesion Molecule-1); 130068-27-8 (Interleukin-10); EC 1.11.1.7 (Peroxidase); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161208
[St] Status:MEDLINE
[do] DOI:10.1007/s10103-016-2115-4


  4 / 905 MEDLINE  
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[PMID]:27587584
[Au] Autor:Hou C; Weidenbach S; Cano KE; Wang Z; Mitra P; Ivanov DN; Rohr J; Tsodikov OV
[Ad] Endereço:Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
[Ti] Título:Structures of mithramycin analogues bound to DNA and implications for targeting transcription factor FLI1.
[So] Source:Nucleic Acids Res;44(18):8990-9004, 2016 Oct 14.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Transcription factors have been considered undruggable, but this paradigm has been recently challenged. DNA binding natural product mithramycin (MTM) is a potent antagonist of oncogenic transcription factor EWS-FLI1. Structural details of MTM recognition of DNA, including the FLI1 binding sequence GGA(A/T), are needed to understand how MTM interferes with EWS-FLI1. We report a crystal structure of an MTM analogue MTM SA-Trp bound to a DNA oligomer containing a site GGCC, and two structures of a novel analogue MTM SA-Phe in complex with DNA. MTM SA-Phe is bound to sites AGGG and GGGT on one DNA, and to AGGG and GGGA(T) (a FLI1 binding site) on the other, revealing how MTM recognizes different DNA sequences. Unexpectedly, at sub-micromolar concentrations MTMs stabilize FLI1-DNA complex on GGAA repeats, which are critical for the oncogenic function of EWS-FLI1. We also directly demonstrate by nuclear magnetic resonance formation of a ternary FLI1-DNA-MTM complex on a single GGAA FLI1/MTM binding site. These biochemical and structural data and a new FLI1-DNA structure suggest that MTM binds the minor groove and perturbs FLI1 bound nearby in the major groove. This ternary complex model may lead to development of novel MTM analogues that selectively target EWS-FLI1 or other oncogenic transcription factors, as anti-cancer therapeutics.
[Mh] Termos MeSH primário: DNA/química
Plicamicina/química
Proteína Proto-Oncogênica c-fli-1/química
[Mh] Termos MeSH secundário: Sequência de Bases
DNA/metabolismo
Modelos Moleculares
Conformação Molecular
Estrutura Molecular
Oligodesoxirribonucleotídeos/química
Oligodesoxirribonucleotídeos/metabolismo
Plicamicina/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Proteína Proto-Oncogênica c-fli-1/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligodeoxyribonucleotides); 0 (Proto-Oncogene Protein c-fli-1); 9007-49-2 (DNA); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160903
[St] Status:MEDLINE


  5 / 905 MEDLINE  
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[PMID]:27537898
[Au] Autor:Ratovitski EA
[Ad] Endereço:Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. eratovi1@jhmi.edu.
[Ti] Título:Tumor Protein (TP)-p53 Members as Regulators of Autophagy in Tumor Cells upon Marine Drug Exposure.
[So] Source:Mar Drugs;14(8), 2016 Aug 16.
[Is] ISSN:1660-3397
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Targeting autophagic pathways might play a critical role in designing novel chemotherapeutic approaches in the treatment of human cancers, and the prevention of tumor-derived chemoresistance. Marine compounds were found to decrease tumor cell growth in vitro and in vivo. Some of them were shown to induce autophagic flux in tumor cells. In this study, we observed that the selected marine life-derived compounds (Chromomycin A2, Psammaplin A, and Ilimaquinone) induce expression of several autophagic signaling intermediates in human squamous cell carcinoma, glioblastoma, and colorectal carcinoma cells in vitro through a transcriptional regulation by tumor protein (TP)-p53 family members. These conclusions were supported by specific qPCR expression analysis, luciferase reporter promoter assay, and chromatin immunoprecipitation of promoter sequences bound to the TP53 family proteins, and silencing of the TP53 members in tumor cells.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Organismos Aquáticos/química
Autofagia/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/isolamento & purificação
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Imunoprecipitação da Cromatina
Dissulfetos/química
Dissulfetos/isolamento & purificação
Dissulfetos/farmacologia
Seres Humanos
Plicamicina/análogos & derivados
Plicamicina/química
Plicamicina/isolamento & purificação
Plicamicina/farmacologia
Quinonas/química
Quinonas/isolamento & purificação
Quinonas/farmacologia
Interferência de RNA
RNA Interferente Pequeno/genética
Reação em Cadeia da Polimerase em Tempo Real
Sesquiterpenos/química
Sesquiterpenos/isolamento & purificação
Sesquiterpenos/farmacologia
Proteína Supressora de Tumor p53/genética
Tirosina/análogos & derivados
Tirosina/química
Tirosina/isolamento & purificação
Tirosina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Disulfides); 0 (Quinones); 0 (RNA, Small Interfering); 0 (Sesquiterpenes); 0 (Tumor Suppressor Protein p53); 0 (chromomycin A2); 110659-91-1 (psammaplin A); 42HK56048U (Tyrosine); 5U0WAN3N8Q (ilimaquinone); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160819
[St] Status:MEDLINE


  6 / 905 MEDLINE  
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[PMID]:27278128
[Au] Autor:Marek-Bukowiec K; Aguado E; Miazek A
[Ad] Endereço:Department of Tumor Immunology, Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.
[Ti] Título:Phorbol ester-mediated re-expression of endogenous LAT adapter in J.CaM2 cells: a model for dissecting drivers and blockers of LAT transcription.
[So] Source:Genes Immun;17(5):313-20, 2016 Jul.
[Is] ISSN:1476-5470
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Linker for activation of T cells (LAT) is a raft-associated, transmembrane adapter protein critical for T-cell development and function. LAT expression is transiently upregulated upon T-cell receptor (TCR) engagement, but molecular mechanisms conveying TCR signaling to enhanced LAT transcription are not fully understood. Here we found that a Jurkat subline J.CaM2, initially characterized as LAT deficient, conditionally re-expressed LAT upon the treatment with a protein kinase C activator, phorbol 12-myristate 13-acetate (PMA). We took advantage of the above observation for studying cis-elements and trans-acting factors contributing to the activation-induced expression of LAT. We identified a LAT gene region spanning nucleotide position -14 to +357 relative to the ATG start codon as containing novel cis-regulatory elements that were able to promote PMA-induced reporter transcription in the absence of the core LAT promoter. Interestingly, a point mutation in LAT intron 1, identified in J.CaM2 cells, downmodulated LAT promoter activity by 50%. Mithramycin A, a selective Sp1 DNA-binding inhibitor, abolished LAT expression upon PMA treatment as did calcium ionophore ionomycin (Iono) and valproic acid (VPA), widely used as an anti-epileptic drug. Our data introduce J.CaM2 cells as a model for dissecting drivers and blockers of activation induced expression of LAT.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas de Membrana/metabolismo
Ésteres de Forbol/farmacologia
Fator de Transcrição Sp1/metabolismo
Ativação Transcricional/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética
Técnicas de Cultura de Células/métodos
Seres Humanos
Íntrons
Ionomicina/farmacologia
Células Jurkat
Proteínas de Membrana/genética
Plicamicina/farmacologia
Mutação Puntual
Regiões Promotoras Genéticas
Fator de Transcrição Sp1/genética
Ácido Valproico/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (LAT protein, human); 0 (Membrane Proteins); 0 (Phorbol Esters); 0 (Sp1 Transcription Factor); 56092-81-0 (Ionomycin); 614OI1Z5WI (Valproic Acid); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170518
[Lr] Data última revisão:
170518
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160610
[St] Status:MEDLINE
[do] DOI:10.1038/gene.2016.25


  7 / 905 MEDLINE  
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[PMID]:27268079
[Au] Autor:Tominaga T; Tsuchiya T; Mochinaga K; Arai J; Yamasaki N; Matsumoto K; Miyazaki T; Nagasaki T; Nanashima A; Tsukamoto K; Nagayasu T
[Ad] Endereço:Division of Surgical Oncology, Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Nagasaki, 852-8501, Japan.
[Ti] Título:Epidermal growth factor signals regulate dihydropyrimidine dehydrogenase expression in EGFR-mutated non-small-cell lung cancer.
[So] Source:BMC Cancer;16:354, 2016 06 06.
[Is] ISSN:1471-2407
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: It has been shown that epidermal growth factor receptor (EGFR) mutation status is associated with 5-fluorouracil (5-FU) sensitivity in non-small-cell lung cancer (NSCLC). However, the relationship between EGFR mutation status and dihydropyrimidine dehydrogenase (DPD), a 5-FU degrading enzyme, is unknown. METHODS: We elucidated the crosstalk among the EGFR signal cascade, the DPD gene (DPYD), and DPD protein expression via the transcription factor Sp1 and the effect of EGFR mutation status on the crosstalk. RESULTS: In the PC9 (exon19 E746-A750) study, EGF treatment induced up-regulation of both Sp1 and DPD; gefitinib, an EGFR-tyrosine kinase inhibitor (EGFR-TKI), and mithramycin A, a specific Sp-1 inhibitor, suppressed them. Among EGFR-mutated (PC9, HCC827; exon19 E746-A750 and H1975; exon21 L858R, T790M, gefitinib resistant) and -non-mutated (H1437, H1299) cell lines, EGF administration increased DPYD mRNA expression only in mutated cells (p < 0.05). Accordingly, gefitinib inhibited DPD protein expression only in PC9 and HCC827 cells, and mithramycin A inhibited it in EGFR-mutated cell lines, but not in wild-type. FU treatment decreased the level of cell viability more in gefitinib-treated EGFR-TKI sensitive cell lines. Further, combination treatment of FU and mithramycin A suppressed cell viability even in a gefitinib resistant cell line. CONCLUSIONS: The EGFR signal cascade regulates DPD expression via Sp1 in EGFR mutant cells. These results might be a step towards new therapies targeting Sp1 and DPD in NSCLC with different EGFR mutant status.
[Mh] Termos MeSH primário: Carcinoma Pulmonar de Células não Pequenas/genética
Di-Hidrouracila Desidrogenase (NADP)/genética
Di-Hidrouracila Desidrogenase (NADP)/metabolismo
Neoplasias Pulmonares/genética
Receptor do Fator de Crescimento Epidérmico/genética
Fator de Transcrição Sp1/metabolismo
[Mh] Termos MeSH secundário: Carcinoma Pulmonar de Células não Pequenas/metabolismo
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Sinergismo Farmacológico
Fator de Crescimento Epidérmico/farmacologia
Fluoruracila/farmacologia
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Mutação
Plicamicina/análogos & derivados
Plicamicina/farmacologia
Quinazolinas/farmacologia
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Quinazolines); 0 (Sp1 Transcription Factor); 0 (Sp1 protein, human); 62229-50-9 (Epidermal Growth Factor); 97666-60-9 (mithramycin A); EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP)); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); NIJ123W41V (Plicamycin); S65743JHBS (gefitinib); U3P01618RT (Fluorouracil)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171120
[Lr] Data última revisão:
171120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160609
[St] Status:MEDLINE
[do] DOI:10.1186/s12885-016-2392-0


  8 / 905 MEDLINE  
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[PMID]:27256574
[Au] Autor:Ratajewski M; Walczak-Drzewiecka A; Gorzkiewicz M; Salkowska A; Dastych J
[Ad] Endereço:Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodz, Poland; and.
[Ti] Título:Expression of human gene coding RORγT receptor depends on the Sp2 transcription factor.
[So] Source:J Leukoc Biol;100(5):1213-1223, 2016 Nov.
[Is] ISSN:1938-3673
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Th17 cells are involved in the immune response against pathogens, autoimmunity, and tumor progression. The differentiation of human Th17 cells requires the upregulation of RORγT, which in human cells is still not well understood. We identified 2 putative binding motifs for specificity protein transcription factors from the specificity protein/Kruppel-like factor family in the promoter of human RORγT and investigated the involvement of specificity proteins in the transcriptional regulation of this gene. To this end, a human lymphocytic cell line and in vitro-differentiated Th17 cells were used in promoter activity assays, in situ mutagenesis, chromatin immunoprecipitation, and real-time RT-PCR assays. In some experiments, specificity protein expression and activity was inhibited by siRNA and mithramycin A. The results showed that the transcription factor specificity protein 2 recognized binding motifs in the human RORγT promoter, which was critical for maintaining expression. Furthermore, specificity protein 2 was necessary for maximum IL-17 expression in in vitro-differentiated Th17 cells. These observations demonstrate the significant role of specificity protein 2 in the regulation of the Th17 signature transcription factor RORγT and the maintenance of the Th17 phenotype. The findings also suggest that specificity protein 2 plays a role in Th17-dependent physiologic and pathologic immune responses and might serve as a potential novel target for their modulation.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética
Regiões Promotoras Genéticas/genética
Fator de Transcrição Sp2/fisiologia
Células Th17/metabolismo
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Sítios de Ligação
Imunoprecipitação da Cromatina
Sequência Conservada
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Interleucina-17/biossíntese
Interleucina-17/genética
Células Jurkat
Mamíferos/genética
Mutagênese Sítio-Dirigida
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/biossíntese
Plicamicina/análogos & derivados
Plicamicina/farmacologia
Regiões Promotoras Genéticas/efeitos dos fármacos
RNA Interferente Pequeno/genética
Reação em Cadeia da Polimerase em Tempo Real
Alinhamento de Sequência
Homologia de Sequência do Ácido Nucleico
Células Th17/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Interleukin-17); 0 (Nuclear Receptor Subfamily 1, Group F, Member 3); 0 (RNA, Small Interfering); 0 (RORC protein, human); 0 (SP2 protein, human); 148710-93-4 (Sp2 Transcription Factor); 97666-60-9 (mithramycin A); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160604
[St] Status:MEDLINE


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[PMID]:27072684
[Au] Autor:Wei C; Zhang W; Zhou Q; Zhao C; Du Y; Yan Q; Li Z; Miao J
[Ad] Endereço:Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, 710038, Shaanxi Province, China.
[Ti] Título:Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.
[So] Source:Neurochem Res;41(8):1924-38, 2016 Aug.
[Is] ISSN:1573-6903
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aß levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aß production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3ß signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.
[Mh] Termos MeSH primário: Doença de Alzheimer/tratamento farmacológico
Doença de Alzheimer/patologia
Transtornos Cognitivos/tratamento farmacológico
Transtornos Cognitivos/patologia
Modelos Animais de Doenças
Plicamicina/análogos & derivados
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Animais
Córtex Cerebral/efeitos dos fármacos
Córtex Cerebral/metabolismo
Córtex Cerebral/patologia
Transtornos Cognitivos/metabolismo
Hipocampo/efeitos dos fármacos
Hipocampo/metabolismo
Hipocampo/patologia
Masculino
Camundongos
Camundongos Transgênicos
Plicamicina/farmacologia
Plicamicina/uso terapêutico
Fator de Transcrição Sp1/antagonistas & inibidores
Fator de Transcrição Sp1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Sp1 Transcription Factor); 97666-60-9 (mithramycin A); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160414
[St] Status:MEDLINE
[do] DOI:10.1007/s11064-016-1903-3


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[PMID]:27004687
[Au] Autor:Wang J; Song W
[Ad] Endereço:Department of Psychiatry, Townsend Family Laboratories, Graduate Program in Neuroscience, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, V6T 1Z3, Canada.
[Ti] Título:Regulation of LRRK2 promoter activity and gene expression by Sp1.
[So] Source:Mol Brain;9:33, 2016 Mar 22.
[Is] ISSN:1756-6606
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The dopaminergic neurodegeneration in the nigrostriatal pathway is a prominent neuropathological feature of Parkinson's disease (PD). Mutations in various genes have been linked to familial PD, and leucine-rich repeat kinase 2 (LRRK2) gene is one of them. LRRK2 is a large complex protein, belonging to the ROCO family of proteins. Recent studies suggest that the level of LRRK2 protein is one of the contributing factors to PD pathogenesis. However, it remains elusive how LRRK2 is regulated at the transcriptional and translational level. RESULTS: In this study, we cloned a 1738 bp 5'-flanking region of the human LRRK2 gene. The transcriptional start site (TSS) was located to 135 bp upstream of translational start site and the fragment -118 to +133 bp had the minimum promoter activity required for transcription. There were two functional Sp1- responsive elements on the human LRRK2 gene promoter revealed by electrophoretic mobility shift assay (EMSA). Sp1 overexpression promoted LRRK2 transcription and translation in the cellular model. On the contrary, application of mithramycin A inhibited LRRK2 transcriptional and translational activities. CONCLUSION: This is the first study indicating that Sp1 signaling plays an important role in the regulation of human LRRK2 gene expression. It suggests that controlling LRRK2 level by manipulating Sp1 signaling may be beneficial to attenuate PD-related neuropathology.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Regiões Promotoras Genéticas
Proteínas Serina-Treonina Quinases/genética
Fator de Transcrição Sp1/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Sítios de Ligação
Clonagem Molecular
Células HEK293
Seres Humanos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina
Dados de Sequência Molecular
Plicamicina/análogos & derivados
Plicamicina/farmacologia
Proteínas Serina-Treonina Quinases/metabolismo
Deleção de Sequência
Sítio de Iniciação de Transcrição
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Sp1 Transcription Factor); 97666-60-9 (mithramycin A); EC 2.7.11.1 (LRRK2 protein, human); EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); NIJ123W41V (Plicamycin)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160324
[St] Status:MEDLINE
[do] DOI:10.1186/s13041-016-0215-5



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