Transcriptional coactivators such as p300 and CREB-binding protein (CBP) function as important elements in the transcription factor network, linking individual transactivators via protein-protein interactions to the basal transcriptional machinery. We have investigated whether p300 plays a role in transactivation mediated by C/EBP␤, a conserved member of the C/EBP family. We show that C/EBP␤-dependent transactivation is strongly inhibited by adenovirus E1A but not by E1A mutants defective in p300 binding. Ectopic expression of p300 reverses the E1A-dependent inhibition and increases the transactivation potential of C/EBP␤. Furthermore, we show that C/EBP␤ and p300 interact with each other and demonstrate that the sequences responsible for interaction map to the E1A binding region of p300 and the amino terminus of C/EBP␤. Finally, we show that the minimal C/EBP␤ binding site of p300 acts as a dominant-negative inhibitor of C/EBP␤. These observations identify p300 as a bona fide coactivator for C/EBP␤. C/EBP␤ is highly expressed in the myelomonocytic lineage of the hematopoietic system and cooperates with Myb to activate mim-1, a gene specifically expressed during myelomonocytic differentiation. Recent evidence has shown that Myb recruits CBP (and presumably p300) as a coactivator and, in contrast to C/EBP␤, interacts with the CREB binding site of p300-CBP. We show that p300 not only stimulates the activity of Myb and C/EBP␤ individually but also increases the synergy between them. Thus, our results reveal a novel function of p300: in addition to linking specific transcription factors to the basal transcriptional machinery, p300 also mediates the cooperation between transactivators interacting with different domains of p300.Initiation of transcription by RNA polymerase II involves the cooperation of transcription factors, binding to specific regulatory sequences, with the basal transcriptional machinery. The transcriptional coactivators p300 and the CREB-binding protein (CBP) have been recognized as key molecules involved in the communication between transcription factors and the transcriptional machinery and thus appear to be important elements of gene regulation networks (for a review, see reference 22). p300 was originally identified as a cellular interaction partner of the adenovirus E1A oncoprotein (17), and inactivation of p300 by binding to E1A appears to be one of the mechanisms by which the E1A protein suppresses transcriptional activation of certain promoters (for a review, see reference 35). Since p300 has strong sequence similarity to CBP and exhibits properties similar to those of CBP, p300 and CBP are considered functional homologs (2, 33). Several transcription factors, such as CREB, Jun, Myb, Sap-1a/Elk-1, Fos, p53, MyoD, and the nuclear hormone receptors, have now been shown to require p300 and CBP as coactivators (3-5, 10, 13, 14, 21, 23, 24, 28, 31, 42, 53). p300 and CBP do not by themselves interact with specific DNA sequences; rather, they display a variety of protein interaction surfaces tha...

T-box genes encode transcription factors that regulate a variety of developmental processes. In this report, we describe the cloning and expression analysis of the novel mouse T-box gene Tbx18. During development expression is most prominent in the proepicardial organ and in the epicardium of the heart. Other sites of expression include the cranial paraxial mesoderm, the presomitic mesoderm, the anterior somite half, the genital ridge, and the developing limb buds.

During early limb development several signaling centers coordinate limb bud outgrowth as well as patterning. Members of the T-box gene family of transcriptional regulators are crucial players in these processes by activating and interpreting these signaling pathways. Here, we show that Tbx15, a member of this gene family, is expressed during limb development, first in the mesenchyme of the early limb bud, then during early endochondral bone development in prehypertrophic chondrocytes of cartilaginous templates. Expression is also found in mesenchymal precursor cells and prehypertrophic chondrocytes, respectively, during development of skeletal elements of the vertebral column and the head. Analysis of Tbx15 null mutant mice indicates a role of Tbx15 in the development of skeletal elements throughout the body. Mutants display a general reduction of bone size and changes of bone shape. In the forelimb skeleton, the scapula lacks the central region of the blade. Cartilaginous templates are already reduced in size and show a transient delay in ossification in mutant embryos. Mutants show a significantly reduced proliferation of prehypertrophic chondrocytes as well as of mesenchymal precursor cells. These data suggest that Tbx15 plays an important role in the development of the skeleton of the limb, vertebral column and head by controlling the number of mesenchymal precursor cells and chondrocytes.

T-box genes constitute a conserved multi-gene family with important roles in many developmental processes. In this report, we describe the cloning and expression analysis of a novel mouse T-box gene, Tbx20. Expression is prominent in the extraembryonic mesoderm, in the developing heart, the eye anlage and motor neurons of hindbrain and spinal cord.

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