RESUMEN
The androgen receptor (AR) is a ligand-dependent transcription factor that plays a crucial role in the development and homeostasis of the prostate and in prostate cancer. The transcriptional activity of AR is mediated by interaction with multiple co-activators, which serve in chromatin modification or remodeling, or provide a link between specific and general transcription factors. We have identified zipper interacting protein (ZIP) kinase as a novel transcriptional co-activator of the AR. ZIP kinase enhanced expression of AR-responsive promotor/luciferase reporter constructs in a hormone- and kinase-dependent manner. Similar results were obtained for glucocorticoid receptor but not for progesterone receptor and estrogen receptor. Following hormone treatment, AR and ZIP kinase formed physical complexes and associated with the promoter and enhancer of the prostate-specific antigen gene, as revealed by chromatin immunoprecipitation. Strikingly, depletion of ZIP kinase by siRNA led to significant reduction of AR-mediated transactivation. The interaction of ZIP kinase with AR seems to be mediated in part by apoptosis antagonizing transcription factor and in part by direct binding. Interestingly, AR was not phosphorylated by ZIP kinase in vitro, suggesting that it phosphorylates other co-activators or chromatin proteins.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/fisiología , Proteínas Quinasas Dependientes de Calcio-Calmodulina/fisiología , Receptores Androgénicos/fisiología , Transcripción Genética , Activación Transcripcional , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Células Cultivadas , Proteínas Quinasas Asociadas a Muerte Celular , Elementos de Facilitación Genéticos , Humanos , Regiones Promotoras Genéticas , Unión Proteica , Ratas , Receptores Androgénicos/metabolismo , Proteínas Represoras/metabolismo , Proteínas Represoras/fisiología , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiologíaRESUMEN
Ehlers-Danlos Syndrome (EDS) type IV is a rare genetic disorder of connective tissue. Most patients with EDS type IV are frequently unaware of this disorder until the catastrophic rupture of an artery or bowel occurs. We are reporting an association between this and another uncommon autosomal dominant disorder, Charcot Marie Tooth disease. The neurologic problem led to painful foot deformities, requiring surgery, which was complicated by difficulty controlling bleeding in the friable tissues. Other reported associations of heritable disorders of connective tissue and neuropathies are described.