RESUMEN
The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
Asunto(s)
Genética Médica/organización & administración , Genoma Humano/genética , Genómica/organización & administración , Cooperación Internacional , Neoplasias/genética , Metilación de ADN , Análisis Mutacional de ADN/tendencias , Bases de Datos Genéticas , Genes Relacionados con las Neoplasias/genética , Genética Médica/tendencias , Genómica/tendencias , Humanos , Propiedad Intelectual , Mutación , Neoplasias/clasificación , Neoplasias/patología , Neoplasias/terapiaRESUMEN
Ligand-bound receptors of the Transforming Growth Factor-beta (TGF-beta) family promote the formation of complexes between Smad proteins that subsequently accumulate in the nucleus and interact there with other transcriptional regulators, leading to modulation of target gene expression. We identified a novel nuclear protein, Smicl, which binds to Smad proteins. Smicl and Smads cooperate and enhance TGF-beta mediated activation of a Smad-responsive reporter gene. A domain with five CCCH-type zinc fingers in Smicl is structurally and functionally, at least in vitro, similar to a domain in CPSF-30, the 30 kDa subunit of Cleavage and Polyadenylation Specificity Factor (CPSF). Like CPSF-30, Smicl can associate with some other CPSF subunits characterized previously. Its effect on the induction of a reporter gene for TGF-beta requires the cleavage/polyadenylation signal downstream of the coding sequence of that gene. Thus, Smicl is a novel protein that displays CPSF-30-like activities, interacts in the nucleus with activated Smads, and potentiates in TGF-beta stimulated cells Smad-dependent transcriptional responses, possibly in conjunction with the activity of CPSF complexes.
Asunto(s)
Proteínas Portadoras/metabolismo , Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Activinas Tipo I/metabolismo , Animales , Secuencia de Bases , Células CHO , Células COS , Proteínas Portadoras/química , Células Cultivadas , Chlorocebus aethiops , Factor de Especificidad de Desdoblamiento y Poliadenilación/química , Clonación Molecular , Cricetinae , Humanos , Ratones , Modelos Biológicos , Datos de Secuencia Molecular , Proteínas Nucleares/química , Precursores del ARN/metabolismo , Homología de Secuencia de Aminoácido , Transducción de Señal , Factores de Tiempo , Transcripción Genética , Transfección , Factor de Crecimiento Transformador beta/metabolismo , Técnicas del Sistema de Dos HíbridosRESUMEN
We, amongst others, have shown that CC homozygosity at the -22C>T promoter polymorphism in presenilin 1 (PSEN1) is associated with increased risk for Alzheimer's disease (AD). Also, studies in AD brains suggested that CC homozygosity increased the risk for AD by increasing the Abeta load. We characterized the PSEN1 promoter by deletion mapping, and analysed the effect of the -22C and -22T alleles on the transcriptional activity of PSEN1 in a transient transfection system. We showed a neuron-specific 2-fold decrease in promoter activity for the -22C risk allele, which in homozygous individuals would lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13 bp region (-33/-20) spanning the -22C>T polymorphism harbours a binding site for a negative regulatory factor. This factor has a higher affinity for the -22C risk allele and is strongly dependent on downstream sequences for cell-type-specific expression differences. Together, these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons.