RESUMO
Thyroid hormone (T3) suppresses cerebral gene expression of the ß-amyloid precursor protein (APP), an integral membrane protein that plays a key role in the onset and progression of Alzheimer's disease. However, the mechanisms by which T3 signaling pathways inhibit APP gene transcription in the brain remain unclear. By carrying out chromatin immunoprecipitation with neuroblastoma cells and primary rat brain tissue, we show for the first time that thyroid hormone receptors (TRs) directly bind at the APP gene in vivo at a promoter region containing a negative T3-response element. We further show that T3 treatment decreases both histone H3 acetylation and histone H3 lysine 4 methylation at the APP promoter and that chemical inhibitors of histone deacetylases and histone lysine demethylase abrogate T3-dependent APP silencing. Our findings thus suggest that TRs actively facilitate T3-dependent silencing of APP gene expression via the recruitment of distinct histone modifying enzymes associated with transcriptional repression.
Assuntos
Precursor de Proteína beta-Amiloide/genética , Encéfalo/metabolismo , Epigênese Genética , Tri-Iodotironina/fisiologia , Acetilação , Doença de Alzheimer , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Histona Desmetilases/antagonistas & inibidores , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Metilação , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Ratos , Ratos Sprague-Dawley , Receptores dos Hormônios Tireóideos/metabolismo , Tranilcipromina/farmacologia , Tri-Iodotironina/farmacologiaRESUMO
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Piridinas/síntese química , Piridonas/síntese química , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Transplante de Neoplasias , Piridinas/química , Piridinas/farmacologia , Piridonas/química , Piridonas/farmacologia , Ratos , Receptor de Insulina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Significant evidence has accumulated suggesting that the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin biosynthetic pathway, plays an important role in tumor development. To better understand the role of COX-2 in tumorigenesis, we generated transgenic mice that overexpress COX-2 under control of the human keratin 14 promoter, which allows for expression in the epidermis and some other epithelia. Transgenic mice, referred to as K14.COX2 mice, were readily distinguished from their nontransgenic littermates by the appearance of significant alopecia. Administration of a specific COX-2 inhibitor restored hair growth, indicating that the alopecia was attributable to elevated COX-2 enzymatic activity. Unexpectedly, COX-2 overexpression was found to protect, rather than sensitize, K14.COX2 mice to skin tumor development induced by an initiation/promotion protocol. K14.COX2 transgenics developed tumors at a much lower frequency than did their littermate controls (3.3% versus 93%, respectively, on a FVB background and approximately 25% versus 100%, respectively, on an ICR background) and presented with significantly reduced tumor burdens (average, 0.03 versus 12.7 tumors/mouse, respectively, on a FVB background and 0.5 versus 7.1 tumors/mouse, respectively, on an ICR background). Mice fed a COX-2 inhibitor in utero and as weanlings up to the time of promotion also showed a significant resistance to tumor development. These results clearly raise questions regarding the role of COX-2 and elevated prostaglandin levels in skin tumor development.