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1.
Oncogene ; 36(9): 1245-1255, 2017 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-27546620

RESUMO

Liver kinase B1 (LKB1) is mutationally inactivated in Peutz-Jeghers syndrome and in a variety of cancers including human papillomavirus (HPV)-caused cervical cancer. However, the significance of LKB1 mutations in cervical cancer initiation and progress has not been examined. Herein, we demonstrated that, in mouse embryonic fibroblasts, loss of LKB1 and transduction of HPV16 E6/E7 had an additive effect on constraining cell senescence while promoting cell proliferation and increasing glucose consumption, lactate production and ATP generation. Knockdown of LKB1 increased and ectopic expression of LKB1 decreased glycolysis, anchorage-independent cell growth, and cell migration and invasion in HPV-transformed cells. In the tumorigenesis and lung metastasis model in syngeneic mice, depletion of LKB1 markedly increased tumor metastatic colonies in lungs without affecting subcutaneous tumor growth. We showed that HPV16 E6/E7 enhanced the expression of hexokinase-ll (HK-II) in the glycolytic pathway through elevated c-MYC. Ectopic LKB1 reduced HK-II along with glycolysis. The inverse relationship between HK-II and LKB1 was also observed in normal and HPV-associated cervical lesions. We propose that LKB1 acts as a safeguard against HPV-stimulated aerobic glycolysis and tumor progression. These findings may eventually aid in the development of therapeutic strategy for HPV-associated malignancies by targeting cell metabolism.


Assuntos
Transformação Celular Neoplásica/metabolismo , Glucose/metabolismo , Glicólise/fisiologia , Infecções por Papillomavirus/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Transformação Celular Neoplásica/patologia , Feminino , Seguimentos , Hexoquinase/genética , Hexoquinase/metabolismo , Papillomavirus Humano 16/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Estadiamento de Neoplasias , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/virologia
2.
Oncogene ; 34(29): 3848-59, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25263448

RESUMO

Liver kinase B1 (LKB1, also known as serine/threonine kinase 11, STK11) is a tumor suppressor mutated in Peutz-Jeghers syndrome and in a variety of sporadic cancers. Herein, we demonstrate that LKB1 controls the levels of intracellular reactive oxygen species (ROS) and protects the genome from oxidative damage. Cells lacking LKB1 exhibit markedly increased intracellular ROS levels, excessive oxidation of DNA, increased mutation rates and accumulation of DNA damage, which are effectively prevented by ectopic expression of LKB1 and by incubation with antioxidant N-acetylcysteine. The role of LKB1 in suppressing ROS is independent of AMP-activated protein kinase, a canonical substrate of LKB1. Instead, under the elevated ROS, LKB1 binds to and maintains the activity of the cdc42-PAK1 (p21-activated kinase 1) complex, which triggers the activation of p38 and its downstream signaling targets, such as ATF-2, thereby enhancing the activity of superoxide dismutase-2 and catalase, two antioxidant enzymes that protect the cells from ROS accumulation, DNA damage and loss of viability. Our results provide a new paradigm for a non-canonical tumor suppressor function of LKB1 and highlight the importance of targeting ROS signaling as a potential therapeutic strategy for cancer cells lacking LKB1.


Assuntos
Dano ao DNA , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Proteínas Quinases Ativadas por AMP , Acetilcisteína/farmacologia , Fator 2 Ativador da Transcrição/metabolismo , Animais , Western Blotting , Catalase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Embrião de Mamíferos/citologia , Ativação Enzimática/efeitos dos fármacos , Fibroblastos/metabolismo , Sequestradores de Radicais Livres/farmacologia , Células HeLa , Humanos , Camundongos Knockout , Microscopia de Fluorescência , Ligação Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Interferência de RNA , Superóxido Dismutase/metabolismo , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo
3.
J Fish Dis ; 38(9): 771-86, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25219871

RESUMO

In many countries, infectious diseases are a considerable threat to aquaculture. The pathogenicity of micro-organisms that infect aquaculture systems is closely related to the release of virulence factors and the formation of biofilms, both of which are regulated by quorum sensing (QS). Thus, QS disruption is a potential strategy for preventing disease in aquaculture systems. QS inhibitors (QSIs) not only inhibit the expression of virulence-associated genes but also attenuate the virulence of aquaculture pathogens. In this review, we discuss QS systems in important aquaculture pathogens and focus on the relationship between QS mechanisms and bacterial virulence in aquaculture. We further elucidate QS disruption strategies for targeting aquaculture pathogens. Four main types of QSIs that target aquaculture pathogens are discussed based on their mechanisms of action.


Assuntos
Aquicultura , Infecções Bacterianas/veterinária , Doenças dos Peixes/prevenção & controle , Percepção de Quorum/fisiologia , Animais , Bactérias/genética , Bactérias/patogenicidade , Infecções Bacterianas/microbiologia , Infecções Bacterianas/prevenção & controle , Clorófitas/fisiologia , Doenças dos Peixes/microbiologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Percepção de Quorum/genética , Fatores de Virulência/genética
4.
Lett Appl Microbiol ; 45(5): 508-14, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17958556

RESUMO

AIMS: To investigate antifungal activity of a novel compound (named as CF66I provisionally) against plant pathogenic fungi, mainly including Fusarium sp., Colletotrichum lindemuthianum, Rhizoctonia solani, etc. METHODS AND RESULTS: Minimal inhibition concentrations (MIC) and minimal fungicidal concentrations (MFC) of CF66I for each fungi were determined using serial broth dilution method. The data demonstrated MIC ranged from 2.5 to 20.0 microg ml(-1) and MFC were shown at levels of < or =7.5 microg ml(-1) except Fusarium sp. With reverse microscopy, profound morphological alterations of fungal cells were observed after exposure to CF66I. Conidiospores were completely inhibited, and protoplasm aggregated to form chalamydospores because of the changes of cell permeability. Some chalamydospores were broken, suggesting the compound probably possessed strong ability of damaging the cell wall. In addition, CF66I was investigated for its antifungal stability against Curvularia lunata. The results showed CF66I kept strong fungi-static activity over-wide pH range (pH 4-9) and temperature range (from -70 to 120 degrees C). CONCLUSIONS: The compound CF66I exhibited strong and stable broad-spectrum antifungal activity, and had a significant fungicidal effect on fungal cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Results from prebiocontrol evaluations performed to date are probably useful in the search for alternative approaches to controlling serious plant pathogens.


Assuntos
Amidas/farmacologia , Antifúngicos/farmacologia , Burkholderia cepacia/metabolismo , Fungos Mitospóricos/efeitos dos fármacos , Doenças das Plantas/microbiologia , Amidas/isolamento & purificação , Antifúngicos/isolamento & purificação , Testes de Sensibilidade Microbiana , Fungos Mitospóricos/citologia , Temperatura
5.
Appl Microbiol Biotechnol ; 72(6): 1276-84, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16708194

RESUMO

Strain CF-66 with strong antifungal activity against Rhizoctonia solani was isolated from compost samples. It is clearly demonstrated that strain CF-66 is belonging to Burkholderia cepacia complex by the morphological and biochemical tests and 16S rDNA sequence. The B. cepacia complex consists of a group of bacteria currently organized into nine genomovars, among them genomovar II and genomovar III, contain the highly epidemic strains. However, it was known that strain CF-66 is not a member of genomovar II or III of the B. cepacia complex by species-specific polymerase chain reaction assay. In this study, the antifungal compound CF66I produced by strain CF-66 was purified and characterized. Based on the nuclear magnetic resonance, GC-MS spectral and infrared spectral data, CF66I was confirmed to have amide bonds, alpha-methyl fatty acid, bromine, and some structural units such as CH(2)CH(2)O. CF66I is stable to high temperature, proteolytic enzymes, and organic solvents. CF66I inhibit the growth of a variety of plant pathogenic fungi and pathogenic yeast, whereas bacterial cells are unaffected. CF66I mainly reduced hyphal extension rates in a dose-dependent manner and induced severe change in cell morphology that resulted in swelled and formed very short hyphae with multiple branches.


Assuntos
Amidas/isolamento & purificação , Amidas/farmacologia , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Burkholderia cepacia/isolamento & purificação , Burkholderia cepacia/metabolismo , Rhizoctonia/efeitos dos fármacos , Amidas/química , Amidas/metabolismo , Antifúngicos/química , Antifúngicos/metabolismo , Bactérias/efeitos dos fármacos , Técnicas de Tipagem Bacteriana , Composição de Bases , Burkholderia cepacia/classificação , Burkholderia cepacia/citologia , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Estabilidade de Medicamentos , Cromatografia Gasosa-Espectrometria de Massas , Genes de RNAr , Hifas/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Microbiologia do Solo
6.
Appl Microbiol Biotechnol ; 66(6): 702-10, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15517247

RESUMO

A bacterial strain capable of rapidly degrading di-2-ethylhexyl phthalate (DEHP) was isolated from soil and identified as Bacillus subtilis. The organism also utilized di-butyl phthalate, di-ethyl phthalate, di-pentyl phthalate, di-propyl phthalate, and phthalic acid as sole carbon sources; and their biodegradation ratio was over 99%, when the incubation was performed for 5 days at 30 degrees C. The microorganism degraded di-2-ethylhexyl phthalate and di-butyl phthalate through the intermediate formation of mono-2-ethylhexyl phthalate and mono-butyl phthalate, which were then metabolized to phthalic acid and further by a protocatechuate pathway, as evidenced by oxygen uptake studies and GC-MS analysis. The decontamination of soil polluted with di-2-ethylhexyl phthalate by B. subtilis was investigated. Experimental results showed that the strain could degrade about 80% of 5 mM DEHP simply by adding 8% culture medium to soil, indicating that the degradation can occur even when other organisms are present.


Assuntos
Bacillus subtilis/isolamento & purificação , Bacillus subtilis/metabolismo , Dietilexilftalato/análogos & derivados , Dietilexilftalato/metabolismo , Microbiologia do Solo , Bacillus subtilis/classificação , Biodegradação Ambiental , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , DNA Ribossômico/química , DNA Ribossômico/isolamento & purificação , Cromatografia Gasosa-Espectrometria de Massas , Genes de RNAr , Dados de Sequência Molecular , Consumo de Oxigênio , Ácidos Ftálicos/metabolismo , Filogenia , RNA Bacteriano/genética , RNA Ribossômico 16S/genética , Análise de Sequência de DNA
7.
Appl Microbiol Biotechnol ; 62(1): 41-7, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12709834

RESUMO

Cells of Candida krusei capable of producing phytase were immobilized in Ca-alginate gel beads and used for the preparation of myo-inositol phosphates. The immobilization yield was increased about 5-fold after the beads were treated for 96 h at pH 4.0, 4 degrees C. The increased yield was retained, even after 1 month, when the cells were kept at this temperature and pH. No shift in the pH optima of phytase of the immobilized cells was observed, compared with that of free cells. However, the optimum temperature for the enzyme of the immobilized cells was 55 degrees C, which was 15 degrees C higher than that of free cells. The degradation characteristics of the phytate in immobilized cells packed in a glass column (i.d. 1.2 cm, length 20 cm) were investigated. The variation in the composition of the products results from a change in the flow rate of phytate solution (5 mM). At a flow rate of 1.30 ml/min, a mixture of myo-inositol-2-monophosphate, myo-inositol-1,2,5-triphosphate and myo-inositol-1,2,5,6-tetrakisphosphate was produced, in which the latter two were physiologically active. Also, it was found by NMR analysis that the enzyme of this strain produced only one isomer of each of the inositol phosphates, with the exception of myo-inositol pentakisphosphate. Therefore, the pure isomers were easily isolated using ion-exchange chromatography.


Assuntos
6-Fitase/metabolismo , Alginatos/química , Candida/enzimologia , Fosfatos de Inositol/metabolismo , 6-Fitase/biossíntese , Cálcio/metabolismo , Células Imobilizadas , Meios de Cultura , Géis/química , Concentração de Íons de Hidrogênio , Fosfatos de Inositol/biossíntese , Microesferas , Temperatura
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