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Biochim Biophys Acta ; 1819(1): 1-15, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22001530


Human TNFAIP3 interacting protein 1 (TNIP1) has diverse functions including support of HIV replication through its interaction with viral Nef and matrix proteins, reduction of TNFα-induced signaling through its interaction with NF-κB pathway proteins, and corepression of agonist-bound retinoic acid receptors and peroxisome proliferator-activated receptors (PPAR). The wide tissue distribution of TNIP1 provides the opportunity to influence numerous cellular responses in these roles and defining control of TNIP1 expression would be central to improved understanding of its impact on cell function. We cloned 6kb of the human TNIP1 promoter and performed predictive and functional analyses to identify regulatory elements. The promoter region proximal to the transcription start site is GC-rich without a recognizable TATA box. In contrast to this proximal ~500bp region, 6kb of the promoter increased reporter construct constitutive activity over five-fold. Throughout the 6kb length, in silico analysis identified several potential binding sites for both constitutive and inducible transcription factors; among the latter were candidate NF-κB binding sequences and peroxisome proliferator response elements (PPREs). We tested NF-κB and PPAR regulation of the endogenous TNIP1 gene and cloned promoter by expression studies, electrophoretic mobility shift assays, and chromatin immunoprecipitations. We validated NF-κB sites in the TNIP1 promoter proximal and distal regions as well as one PPRE in the distal region. The ultimate control of the TNIP1 promoter is likely to be a combination of constitutive transcription factors and those subject to activation such as NF-κB and PPAR.

Proteínas de Ligação a DNA/genética , NF-kappa B/genética , PPAR gama/genética , Regiões Promotoras Genéticas , Sequências Reguladoras de Ácido Nucleico/genética , Sequência de Bases , Sítios de Ligação , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Dados de Sequência Molecular , NF-kappa B/metabolismo , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ligação Proteica/genética , Elementos de Resposta/genética , Transdução de Sinais , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Sítio de Iniciação de Transcrição , Ativação Transcricional/genética
Bioorg Med Chem Lett ; 20(5): 1744-8, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20153189
Bioorg Med Chem Lett ; 18(5): 1702-7, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18258427


A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.

Benzimidazóis/química , Benzimidazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Ligação Proteica , Soro , Relação Estrutura-Atividade