RESUMO
Lung adenocarcinoma (LUAC) is a unique lung cancer subtype that is responsive to several therapeutic agents. The KRAS gene is the second most frequently mutated gene in LUAC and the majority of KRAS mutations are one of three classical activating mutations (G12, G13, and Q61). Recently, other types of "minor" KRAS mutation have been identified among LUAC patients and some may have similar transforming activities to those of the classical KRAS mutations. Here we describe minor KRAS mutations in LUAC patients, some of which (A66T, A66V, and G75E) may have tumor-forming activity in mouse embryonic fibroblasts in an allograft model. RNA-Seq analysis revealed that mouse embryonic fibroblasts overexpressing these three minor KRAS mutations have distinct expression profiles compared with overexpression of the wild type but similar expression profiles compared with overexpression of the classical KRAS mutants. Our results indicate that some of the minor KRAS mutations cause varying tumor formation activity and are important targets for developing anti-RAS agents as chemotherapeutic agents.
Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Mutação Puntual , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/patologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Modelos Moleculares , TranscriptomaRESUMO
Mitogen-activated protein kinase phosphatase 5 (MKP-5)/DUSP10 acts as a phosphatase of stress-activated kinases (JNK and p38), but its activity towards ERK has not been demonstrated. In the present study we observed that MKP-5 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription. These data suggested a novel MKP-5 function as a scaffold protein for the ERK pathway. We analyzed MKP-5 gene expression in several tumors, and found that it is frequently upregulated in colorectal but not in lung and breast cancer, suggesting its association with the malignant phenotype of colon cancer.
Assuntos
Carcinoma/enzimologia , Neoplasias do Colo/enzimologia , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Linhagem Celular Tumoral , Fosfatases de Especificidade Dupla/genética , Genes Reporter , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Luciferases/biossíntese , Luciferases/genética , Sistema de Sinalização das MAP Quinases , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Elementos de Resposta , Transcrição Gênica , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Cell division cycle 25 (CDC25) phosphatases are cell-cycle regulatory proteins which are overexpressed in a significant number of human cancers. This study evaluated the role of CDC25 phosphatases in human glioma proliferation. Upregulation of CDC25A was observed in human glioma specimens and human glioma cell lines. Comparison of expression levels of CDC25A and CDC25B messenger ribonucleic acid (RNA) to Ki-67 labeling index in glioma tissues found that Ki-67 labeling index was significantly correlated with the expression of CDC25A, but not with that of CDC25B. Depletion of CDC25A by small interfering RNA and inhibition of CDC25 suppressed cell proliferation and induced apoptosis in glioma cell lines, indicating that CDC25A is a potential target for the development of new therapy for glioma.
Assuntos
Neoplasias Encefálicas/metabolismo , Expressão Gênica/fisiologia , Glioma/metabolismo , Antígeno Ki-67/metabolismo , RNA Mensageiro/metabolismo , Estatística como Assunto , Fosfatases cdc25/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzoquinonas/farmacologia , Neoplasias Encefálicas/genética , Caspase 3/metabolismo , Caspase 7/metabolismo , Morte Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Etilaminas/farmacologia , Feminino , Glioma/genética , Humanos , Antígeno Ki-67/genética , Masculino , Pessoa de Meia-Idade , Nitrocompostos/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Tiazóis/farmacologia , Fatores de Tempo , Transfecção/métodos , Regulação para Cima/genética , Adulto Jovem , Fosfatases cdc25/antagonistas & inibidores , Fosfatases cdc25/metabolismoRESUMO
O-acetylserine(thiol) lyase (OASTL), a key enzyme of the plant sulfur assimilatory pathway, catalyses the formation of cysteine from sulfide and O-acetylserine. Transgenic hybrid poplar (Populus sieboldi x P. grandidentata 'Y63') plants expressing cys1, encoding a wheat cytosolic OASTL, were developed in order to examine the role of this enzyme in thiol production following hydrogen sulfide or sulfur dioxide exposure and in the extent of damage induced in the plants by these pollutants. The transgenic cys1 plants accumulated up to several-fold higher cysteine and glutathione levels and were significantly more resistant in terms of foliar damage to the pollutants than WT plants. The transgenic poplar also showed higher tolerance to sulfite and hydrogen peroxide and, interestingly, accumulated several-fold higher sulfite reductase transcripts than WT plants in response to sulfur dioxide. These data clearly demonstrate the important role of OASTL and the sulfur reduction pathway in sulfur and oxidative stress amelioration, and support the notion that transgenic trees resistant to such pollutants can be generated for phytoremediation strategies.
