RESUMEN
Ubiquitin modification of many cellular proteins targets them for proteasomal degradation, but in addition can also serve non-proteolytic functions. Over the last years, a significant progress has been made in our understanding of how modification of the substrates of the ubiquitin system is regulated. However, little is known on how the ubiquitin system that is comprised of â¼1500 components is regulated. Here, we discuss how the biggest subfamily within the system, that of the E3 ubiquitin ligases that endow the system with its high specificity towards the numerous substrates, is regulated and in particular via self-regulation mediated by ubiquitin modification. Ligases can be targeted for degradation in a self-catalyzed manner, or through modification mediated by an external ligase(s). In addition, non-proteolytic functions of self-ubiquitination, for example activation of the ligase, of E3s are discussed.
Asunto(s)
Ubiquitina-Proteína Ligasas , Animales , Activación Enzimática , Humanos , Hidrólisis , Complejo de la Endopetidasa Proteasomal/química , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Especificidad por Sustrato , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina/química , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/fisiología , UbiquitinaciónRESUMEN
The trace metal copper is essential for a variety of biological processes, but extremely toxic when present in excessive amounts. Therefore, concentrations of this metal in the body are kept under tight control. Central regulators of cellular copper metabolism are the copper-transporting P-type ATPases ATP7A and ATP7B. Mutations in ATP7A or ATP7B disrupt the homeostatic copper balance, resulting in copper deficiency (Menkes disease) or copper overload (Wilson disease), respectively. ATP7A and ATP7B exert their functions in copper transport through a variety of interdependent mechanisms and regulatory events, including their catalytic ATPase activity, copper-induced trafficking, post-translational modifications and protein-protein interactions. This paper reviews the extensive efforts that have been undertaken over the past few years to dissect and characterise these mechanisms, and how these are affected in Menkes and Wilson disease. As both disorders are characterised by an extensive clinical heterogeneity, we will discus how the underlying genetic defects correlate with the molecular functions of ATP7A and ATP7B and with the clinical expression of these disorders.
Asunto(s)
Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión/genética , Degeneración Hepatolenticular/genética , Síndrome del Pelo Ensortijado/genética , Adenosina Trifosfatasas/química , Adenosina Trifosfatasas/fisiología , Adenosina Trifosfato/metabolismo , Animales , Proteínas de Transporte de Catión/química , Proteínas de Transporte de Catión/fisiología , Cobre/metabolismo , ATPasas Transportadoras de Cobre , Modelos Animales de Enfermedad , Femenino , Genotipo , Degeneración Hepatolenticular/metabolismo , Humanos , Masculino , Síndrome del Pelo Ensortijado/metabolismo , Ratones , Ratones Mutantes , Mutación Missense , Fenotipo , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Ratas , Ratas Endogámicas LEC , Relación Estructura-Actividad , Pez CebraRESUMEN
Copper is an essential transition metal but is toxic in excess; therefore, its metabolism needs to be tightly regulated. Defects in the regulation of copper can lead to various disorders characterized by copper deficiency or copper excess. Recently, we characterized the COMMD1 (previously MURR1) gene as the defective gene in canine copper toxicosis. The molecular functions of COMMD1 remain unknown, but significant progress has been made in identifying the cellular processes in which COMMD1 participates, through the identification of proteins interacting with COMMD1. This review discusses how COMMD1 functions as a regulator of not only copper homeostasis but also sodium transport and the NF-kappaB signaling pathway. We outline the possible mechanisms through which COMMD1 exerts these newly identified functions.
Asunto(s)
Cobre/metabolismo , Enfermedades de los Perros/genética , Errores Innatos del Metabolismo de los Metales/veterinaria , Proteínas/genética , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Portadoras , Clonación Molecular , Cobre/toxicidad , Perros , Genes Reguladores/fisiología , Hepatocitos/citología , Humanos , Errores Innatos del Metabolismo de los Metales/genética , Modelos Animales , FN-kappa B/fisiología , Proteínas/fisiología , Transducción de Señal/genética , Sodio/metabolismoRESUMEN
Sarcoidosis of the pancreas is a rare entity. We report on the computed tomographic demonstration of multifocal pancreatic involvement in a patient with systemic sarcoidosis.
Asunto(s)
Enfermedades Pancreáticas/diagnóstico por imagen , Sarcoidosis/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Anciano , Biopsia , Líquido del Lavado Bronquioalveolar/citología , Colangiografía , Colangiopancreatografia Retrógrada Endoscópica , Enfermedades de la Vesícula Biliar/diagnóstico por imagen , Humanos , Enfermedades Pulmonares/patología , Masculino , Conductos Pancreáticos/diagnóstico por imagen , Sarcoidosis/patologíaRESUMEN
The history of a man who developed a limited angiitis and granulomatosis of the Wegener type is described. Wegener granulomatosis is a hypersensitivity disease (type III) with an unknown etiology. The typical radiological features, the differential diagnosis and treatment are briefly discussed.
Asunto(s)
Granulomatosis con Poliangitis/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Biopsia , Ciclofosfamida/administración & dosificación , Quimioterapia Combinada , Granulomatosis con Poliangitis/tratamiento farmacológico , Granulomatosis con Poliangitis/patología , Humanos , Pulmón/patología , Masculino , Hemisuccinato de Metilprednisolona/administración & dosificación , Persona de Mediana Edad , RadiografíaRESUMEN
The effects of aqueous extracts of Osbeckia octandra whole plant, Melothria maderaspatana whole plant and Phyllanthus debelis leaves on the human immune system were investigated. The extracts showed strong anticomplement effects on both the classical and alternate pathways of the human complement system in vitro. The effects were dose-dependent and most pronounced in the classical complement pathway assay. The extracts also exhibited a direct dose-dependent inhibition of luminol-induced chemiluminescence of human polymorphonuclear leukocytes upon stimulation with zymosan.