A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis.
The coactivators CBP (Cre-element binding protein (CREB)-binding protein) and its paralogue p300 are thought to supply adaptor molecule and protein acetyltransferase functions to many transcription factors that regulate gene expression. Normal development requires CBP and p300, and mutations in these genes are found in haematopoietic and epithelial tumours. It is unclear, however, which functions of CBP and p300 are essential in vivo. Here we show that the protein-binding KIX domains of CBP and p300 have nonredundant functions in mice. In mice homozygous for point mutations in the KIX domain of p300 designed to disrupt the binding surface for the transcription factors c-Myb and CREB, multilineage defects occur in haematopoiesis, including anaemia, B-cell deficiency, thymic hypoplasia, megakaryocytosis and thrombocytosis. By contrast, age-matched mice homozygous for identical mutations in the KIX domain of CBP are essentially normal. There is a synergistic genetic interaction between mutations in c-Myb and mutations in the KIX domain of p300, which suggests that the binding of c-Myb to this domain of p300 is crucial for the development and function of megakaryocytes. Thus, conserved domains in two highly related coactivators have contrasting roles in haematopoiesis.
Kasper
Lawryn H
LH
Department of Biochemistry, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee 38105, USA.
Boussouar
Fayçal
F
Ney
Paul A
PA
Jackson
Carl W
CW
Rehg
Jerold
J
van Deursen
Jan M
JM
Brindle
Paul K
PK
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D050882:CREB-Binding Protein; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D050881:E1A-Associated p300 Protein; D005434:Flow Cytometry; D006410:Hematopoiesis; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D020598:Proto-Oncogene Proteins c-myb; D015534:Trans-Activators; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse