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Mol Cancer ; 9: 38, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20156337

RESUMO

BACKGROUND: The cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) mediated phosphorylation of glucocorticoid receptor (GR) exerts opposite effects on GR transcriptional activity and affects other posttranslational modifications within this protein. The major phosphorylation site of human GR targeted by MAPK family is the serine 226 and multiple kinase complexes phosphorylate receptor at the serine 211 residue. We hypothesize that GR posttranslational modifications are involved in the determination of the cellular fate in human lymphoblastic leukemia cells. We investigated whether UV signalling through alternative GR phosphorylation determined the cell type specificity of glucocorticoids (GCs) mediated apoptosis. RESULTS: We have identified putative Glucocorticoid Response Elements (GREs) within the promoter regulatory regions of the Bcl-2 family members NOXA and Mcl-1 indicating that they are direct GR transcriptional targets. These genes were differentially regulated in CEM-C7-14, CEM-C1-15 and A549 cells by glucocorticoids and JNK pathway. In addition, our results revealed that the S211 phosphorylation was dominant in CEM-C7-14, whereas the opposite was the case in CEM-C1-15 where prevalence of S226 GR phosphorylation was observed. Furthermore, multiple GR isoforms with cell line specific patterns were identified in CEM-C7-14 cells compared to CEM-C1-15 and A549 cell lines with the same antibodies. CONCLUSIONS: GR phosphorylation status kinetics, and site specificity as well as isoform variability differ in CEM-C7-14, CEM-C1-15, and A549 cells. The positive or negative response to GCs induced apoptosis in these cell lines is a consequence of the variable equilibrium of NOXA and Mcl-1 gene expression potentially mediated by alternatively phosphorylated GR, as well as the balance of MAPK/CDK pathways controlling GR phosphorylation pattern. Our results provide molecular base and valuable knowledge for improving the GC based therapies of leukaemia.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores de Glucocorticoides/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Sequência de Bases , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/metabolismo , Dexametasona/farmacologia , Fase G1/efeitos dos fármacos , Fase G1/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Dados de Sequência Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Especificidade de Órgãos/efeitos dos fármacos , Especificidade de Órgãos/efeitos da radiação , Fosforilação/efeitos dos fármacos , Fosforilação/efeitos da radiação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elementos de Resposta/genética , Raios Ultravioleta
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