The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.
We have investigated the E1A-inducible E3 promoter of adenovirus type 5 with respect to its ability to bind specific nuclear proteins. Four distinct nucleoprotein-binding sites were detected, located between positions -7 to -33, -44 to -68, -81 to -103, and -154 to -183, relative to the E3 cap site. These sites contain sequences previously shown to be functionally important for efficient E3 transcription. No major qualitative or quantitative differences were found in the binding pattern between nucleoprotein extracts prepared from uninfected or adenovirus-infected HeLa cells. Competition experiments suggest that the factors binding to the -154 to -183 and -81 to -103 sites are the previously identified nucleoproteins, NFI and AP1, respectively. The factor binding to the -44 to -68 site, which we term ATF, also interacts with other E1A-inducible promoters and is very similar and probably identical to the factor that binds to the cAMP-responsive element of somatostatin. We have purified this factor, which is a protein of 43 kD in size.
SWI/SNF complexes are ATP-dependent chromatin remodelling enzymes that have been implicated in the regulation of gene expression in yeast and higher eukaryotes. BRG1, a catalytic subunit in the mammalian SWI/SNF complex, is required for transcriptional activation by the estrogen receptor, but the mechanisms by which the complex is recruited to estrogen target genes are unknown. Here, we have identi®ed an interaction between the estrogen receptor and BAF57, a subunit present only in mammalian SWI/SNF complexes, which is stimulated by estrogen and requires both a functional hormone-binding domain and the DNA-binding region of the receptor. We also found an additional interaction between the p160 family of coactivators and BAF57 and demonstrate that the ability of p160 coactivators to potentiate transcription by the estrogen receptor is dependent on BAF57 in transfected cells. Moreover, chromatin immunoprecipitation assays demonstrated that BAF57 is recruited to the estrogen-responsive promoter, pS2, in a liganddependent manner. These results suggest that one of the mechanisms for recruiting SWI/SNF complexes to estrogen target genes is by means of BAF57.
We have examined the relationship between sequence-specific DNA-binding proteins that activate transcription of ElA-inducible adenovirus early promoters. Factors previously referred to as E4F1 and E2A-EF bind to the E4 and E2A promoters, respectively. We demonstrate here that E4F1 and E2A-EF have identical DNA-binding specificity. Moreover, E4F1 and E2A-EF both activate transcription of the E4 and E2A promoters in vitro. These findings demonstrate that E4F1 and E2A-EF are the same factor, which we have designated activating transcription factor, or ATF. In addition to the E4 and E2A promoters, ATF binds to an important functional element of the ElA-inducible E3 promoter. Interaction of a common activator protein, ATF, with multiple ElA-inducible early viral promoters, suggests a significant role for ATF in ElA-mediated transcriptional activation.The EIA gene of adenovirus produces closely related 13S and 12S mRNAs that encode nuclear-localized phosphoproteins with diverse transcriptional regulatory properties (1-3). The EMA 13S gene product coordinately activates a set of viral early genes (EIA, EIB, E2A, E3, and E4) during a productive infection of permissive human cells (4-7). The ElA 12S gene product encodes a transcriptional repression function that appears to act through transcriptional enhancer elements (8-10). In addition to regulating viral transcription, ElA activates or represses transcription of a limited number of cellular genes (11,12), and activates polymerase III-dependent promoters (for review, see ref. E4 and E3 transcription (18, 19). For the EIB promoter (22) and the cellular /-globin promoter (23), the "TATA" box has been implicated as an ElA-responsive promoter element. Thus activation of a variety of ElA-inducible promoters appears to involve different cellular factors and may occur through divergent pathways, ultimately linked by ElA. Two independent studies have identified additional factors that interact with early viral promoters. A factor referred to as E4F1 binds to the E4 promoter and also interacts with the EIA, E2A, and E3 promoters (18). Similarly, a factor referred to as E2A-EF binds to the E2A, EIA, E3, and E4 promoters (17). We show here that E4F1 and E2A-EF have the same DNA-binding specificity and that both factors activate transcription of the E4 and E2A promoters in vitro. These results demonstrate that E4F1 and E2A-EF are the same factor, which we refer to as ATF, for activating transcription factor. In addition to the E4 and E2A promoters, ATF interacts with an important functional element of the adenovirus E3 promoter. The interaction of ATF with multiple ElA-inducible promoters suggests a significant role for ATF in E1A-mediated transcriptional activation. MATERIALS AND METHODSPlasmids. pE4WT contains the adenovirus type 5 genome between map units 100 and 89, including the entire E4 gene cloned into pBR322 between the EcoRI and Pvu II sites.
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