The CBP coactivator functions both upstream and downstream of Dpp/Screw signaling in the early Drosophila embryo.
The CBP histone acetyltransferase plays important roles in development and disease by acting as a transcriptional coregulator. A small reduction in the amount of Drosophila CBP (dCBP) leads to a specific loss of signaling by the TGF-beta molecules Dpp and Screw in the early embryo. We show that the expression of Screw itself, and that of two regulators of Dpp/Screw activity, Twisted-gastrulation and the Tolloid protease, is compromised in dCBP mutant embryos. This prevents Dpp/Screw from initiating a signal transduction event in the receiving cell. Smad proteins, the intracellular transducers of the signal, fail to become activated by phosphorylation in dCBP mutants, leading to diminished Dpp/Screw-target gene expression. At a slightly later stage of development, Dpp/Screw-signaling recovers in dCBP mutants, but without a restoration of Dpp/Screw-target gene expression. In this situation, dCBP acts downstream of Smad protein phosphorylation, presumably via direct interactions with the Drosophila Smad protein Mad. It appears that a major function of dCBP in the embryo is to regulate upstream components of the Dpp/Screw pathway by Smad-independent mechanisms, as well as acting as a Smad coactivator on downstream target genes. These results highlight the exceptional sensitivity of components in the TGF-beta signaling pathway to a decline in CBP concentration.
Lilja
Tobias
T
Department of Developmental Biology, Wenner-Gren Institute, Arrheniuslaboratories E3, Stockholm University, S-106 91, Stockholm, Sweden.
Qi
Dai
D
Stabell
Marianne
M
Mannervik
Mattias
M
D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051548:Histone Acetyltransferases; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D029721:Drosophila Proteins; C090409:SCW protein, Drosophila; D029701:Saccharomyces cerevisiae Proteins; D016212:Transforming Growth Factor beta; C064196:dpp protein, Drosophila; D000123:Acetyltransferases; D051548:Histone Acetyltransferases