RESUMO
Genetic variation in the ADRB2 gene has been hypothesized to have a role in differential response to beta-agonist (BA) therapy in asthma. However, study results have been inconsistent and the issue remains controversial. Furthermore, the impact of ADRB2 genetic variation on BA response in chronic obstructive pulmonary disease (COPD) patients has not been thoroughly studied. We carried out a large pharmacogenetic analysis testing for an association between common ADRB2 polymorphisms and indacaterol response in COPD patients. A total of 648 indacaterol-treated patients enrolled in two large randomized phase III studies were genotyped for the most commonly studied polymorphisms in the ADRB2 gene: Gly16Arg, Gln27Glu, Thr164Ile, and a variant in the 5' untranslated region (rs1042711). Our analysis showed little evidence for the association between these ADRB2 variants and indacaterol response, suggesting that ADRB2 genetic variation is unlikely to have a major role in differential response to indacaterol treatment in COPD patients.
Assuntos
Indanos/uso terapêutico , Polimorfismo Genético , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Receptores Adrenérgicos beta 2/genética , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Adulto , Idoso , Método Duplo-Cego , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Farmacogenética , Doença Pulmonar Obstrutiva Crônica/genética , Estudos RetrospectivosRESUMO
WT1 encodes a zinc finger transcription factor implicated in kidney differentiation and tumorigenesis. In reporter assays, WT1 represses transcription from GC- and TC-rich promoters, but its physiological targets remain uncertain. We used hybridization to high-density oligonucleotide arrays to search for native genes whose expression is altered following inducible expression of WT1. The major target of WT1 was amphiregulin, a member of the epidermal growth factor family. The WT1(-KTS) isoform binds directly to the amphiregulin promoter, resulting in potent transcriptional activation. The in vivo expression profile of amphiregulin during fetal kidney development mirrors the highly specific pattern of WT1 itself, and recombinant Amphiregulin stimulates epithelial branching in organ cultures of embryonic mouse kidney. These observations suggest a model for WT1 as a transcriptional regulator during kidney differentiation.
Assuntos
Proteínas de Ligação a DNA/genética , Glicoproteínas/genética , Substâncias de Crescimento/genética , Peptídeos e Proteínas de Sinalização Intercelular , Fatores de Transcrição/genética , Ativação Transcricional/genética , Anfirregulina , Animais , Sequência de Bases , Pegada de DNA , Proteínas de Ligação a DNA/fisiologia , Relação Dose-Resposta a Droga , Família de Proteínas EGF , Glicoproteínas/farmacologia , Glicoproteínas/fisiologia , Substâncias de Crescimento/farmacologia , Substâncias de Crescimento/fisiologia , Humanos , Rim/anatomia & histologia , Rim/embriologia , Camundongos , Modelos Genéticos , Dados de Sequência Molecular , Mutagênese , Análise de Sequência com Séries de Oligonucleotídeos , Osteossarcoma/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/análise , Elementos de Resposta/genética , Fatores de Tempo , Fatores de Transcrição/fisiologia , Células Tumorais Cultivadas , Ureter/embriologia , Proteínas WT1RESUMO
We have examined regulation of the E2F transcription factor during differentiation of muscle cells. E2F regulates many genes involved in growth control and is also the target of regulation by diverse cellular signals, including the RB family of growth suppressors (e.g., the retinoblastoma protein [RB], p107, and p130). The following aspects of E2F function and regulation during muscle differentiation were investigated: (i) protein-protein interactions, (ii) protein levels, (iii) phosphorylation of the E2F protein, and (iv) transcriptional activity. A distinct E2F complex was present in differentiated cells but not in undifferentiated cells. The p130 protein was a prominent component of the E2F complex associated with differentiation. In contrast, in undifferentiated cells, the p107 protein was the prominent component in one of three E2F complexes. In addition, use of a differentiation-defective muscle line provided genetic and biochemical evidence that quiescence and differentiation are separable events. Exclusive formation of the E2F-p130 complex did not occur in this differentiation-defective line; however, E2F complexes diagnostic of quiescence were readily apparent. Thus, sole formation of the E2F-p130 complex is a necessary event in terminal differentiation. Other changes in E2F function and regulation upon differentiation include decreased phosphorylation and increased repression by E2F. These observations suggest that the regulation of E2F function during terminal differentiation may proceed through differential interaction within the RB family and/or phosphorylation.
