ABSTRACT
CREB binding protein (CBP) functions as an essential coactivator of transcription factors that are inhibited by the adenovirus early gene product E1A. Transcriptional activation by the signal transducer and activator of transcription-1 (STAT1) protein requires the C/H3 domain in CBP, which is the primary target of E1A inhibition. Here it was found that the C/H3 domain is not required for retinoic acid receptor (RAR) function, nor is it involved in E1A inhibition. Instead, E1A inhibits RAR function by preventing the assembly of CBP-nuclear receptor coactivator complexes, revealing differences in required CBP domains for transcriptional activation by RAR and STAT1.
Subject(s)
Adenovirus E1A Proteins/metabolism , Nuclear Proteins/metabolism , Transcription Factors/metabolism , Transcription, Genetic , Adenovirus E1A Proteins/pharmacology , Animals , Binding Sites , CREB-Binding Protein , Cell Differentiation , Cell Line , DNA-Binding Proteins/metabolism , Histone Acetyltransferases , Humans , Mutation , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Nuclear Receptor Coactivator 1 , Nuclear Receptor Coactivator 3 , Protein Binding , Receptors, Retinoic Acid/metabolism , Recombinant Fusion Proteins/metabolism , STAT1 Transcription Factor , Trans-Activators/metabolism , Transcription Factors/chemistry , Transcription Factors/genetics , Transcriptional Activation , Tretinoin/pharmacologyABSTRACT
BACKGROUND: Esophagitis in infants and children is often characterized by eosinophilic inflammation. The underlying pathophysiologic mechanisms leading to this type of inflammation, and the role of eosinophils in the clinical expression of esophagitis, are unknown. The purpose of this study was to demonstrate the ultrastructural activation state of eosinophils in esophagitis in infants and children. METHODS: Standard transmission electron microscopy was used to examine endoscopic esophageal biopsy material from patients with and without esophagitis, as defined by standard histologic criteria. RESULTS: Twelve esophagitis and three control cases were studied. In patients with esophagitis, electron microscopy revealed numerous eosinophils throughout the mucosa and invariably demonstrated signs of activation, including inversion of core-to-matrix densities and lucency of granule core protein. Eosinophils in an activated state were seen in active diapedesis through vascular endothelium into the mucosa. Eosinophils were sometimes seen in proximity to lymphocytes. Biopsies of control patients did not demonstrate eosinophils. CONCLUSIONS: Eosinophils present in esophagitis are activated by electron microscopic criteria, and can been seen in an activated state entering into the mucosa. This suggests that eosinophils play an active role in the pathophysiology of this disorder, and that proinflammatory factors are present that selectively recruit and activate eosinophils in esophagitis in children.
Subject(s)
Eosinophilia/pathology , Eosinophils/physiology , Esophagitis/pathology , Esophagus/pathology , Adolescent , Biopsy , Child , Child, Preschool , Endoscopy, Gastrointestinal , Eosinophils/ultrastructure , Humans , Infant , Microscopy, ElectronABSTRACT
We report that interferon gamma (IFN-gamma) inhibits transcription of the macrophage scavenger receptor gene by antagonizing the Ras-dependent activities of AP-1 and cooperating ets domain transcription factors, apparently as a result of competition between AP-1/ets factors and activated STAT1 for limiting amounts of CBP and p300. Consistent with this model, STAT1 alpha interacts directly with CBP in cells, and microinjection of anti-CBP and anti-p300 antibodies blocks transcriptional responses to IFN-gamma. Cells lacking STAT1 fail to inhibit AP-1/ets activity, and overexpression of CBP both potentiates IFN-gamma-dependent transcription and relieves AP-1/ets repression. Thus, CBP and p300 integrate both positive and negative effects of IFN-gamma on gene expression by serving as essential coactivators of STAT1 alpha, modulating gene-specific responses to simultaneous activation of two or more signal transduction pathways.
