RESUMO
Cytokines play key roles in a variety of reproductive processes including normal parturition as well as preterm birth. Our previous data have shown that MAFF, a member of the MAF family of bZIP transcription factors, is rapidly induced by pro-inflammatory cytokines in PHM1-31 myometrial cells. We performed loss-of-function studies in PHM1-31 cells to identify MAFF dependent genes. We showed that knockdown of MAFF significantly decreased CXCL1 chemokine and CSF3 cytokine transcript and protein levels. Using chromatin immunoprecipitation analyzes, we confirmed CXCL1 and CSF3 genes as direct MAFF targets. We also demonstrated that MAFF function in PHM1-31 myometrial cells is able to control cytokine and matrix metalloproteinase gene expression in THP-1 monocytic cells in a paracrine fashion. Our studies provide valuable insights into the MAFF dependent transcriptional network governing myometrial cell function. The data suggest a role of MAFF in parturition and/or infection-induced preterm labour through modulation of inflammatory processes in the microenvironment.
Assuntos
Quimiocina CXCL1/genética , Fator Estimulador de Colônias de Granulócitos/genética , Fator de Transcrição MafF/genética , Metaloproteinases da Matriz/genética , Miócitos de Músculo Liso/metabolismo , Miométrio/metabolismo , Proteínas Nucleares/genética , Linhagem Celular , Quimiocina CXCL1/metabolismo , Feminino , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/metabolismo , Humanos , Fator de Transcrição MafF/antagonistas & inibidores , Fator de Transcrição MafF/metabolismo , Metaloproteinases da Matriz/metabolismo , Miócitos de Músculo Liso/citologia , Miométrio/citologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Comunicação Parácrina , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Células THP-1 , Transcrição GênicaRESUMO
The small MAFs, MAFF, MAFG and MAFK have emerged as crucial regulators of mammalian gene expression. Previous studies have linked small MAF function, by virtue of their heterodimerization with the Cap 'n' Collar (CNC) family of transcription factors, to the stress response and detoxification pathways. Recent analyses have revealed a complex regulatory network involving small MAF transcription factors and other cellular proteins. The expression and activity of small MAFs are tightly regulated at multiple levels. With regard to their clinical importance, small MAFs have been linked to various diseases, such as diabetes, neuronal disorders, thrombocytopenia and carcinogenesis. A better understanding of the molecular mechanisms governing the activity of small MAFs will provide novel insights into the control of mammalian transcription and may lead to the development of novel therapeutic strategies to treat common human disorders.
Assuntos
Fatores de Transcrição maf Pequeno/metabolismo , Animais , Doença/etiologia , Redes Reguladoras de Genes/genética , Humanos , Inativação Metabólica , Modelos Biológicos , Processamento de Proteína Pós-TraducionalRESUMO
We have constructed a very large virtual diversity space containing more than 10(13) chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.