A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis (original) (raw)

Nature volume 419, pages 738–743 (2002)Cite this article

Abstract

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 expression1. Normal development requires CBP and p300, and mutations in these genes are found in haematopoietic and epithelial tumours2,3,4,5,6. 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 CREB7,8,9, 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.

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Acknowledgements

We thank M. Castor, D. Bush, S. Kelly and M. Harper for technical help; J. Gatewood, M. Paktinat, R. Cross, R. Ashmun and A. Hoffmeyer for FACS analyses; S. Steward and T. Pestina for help with the platelet counts; R. Piekorz for assistance with the bone marrow transplants; X. Xiong and J. Schroeder for advice on statistics; A. Hoffmeyer for discussions; R. Shivdasani for advice on purifying megakaryocytes; H. Singh for c-Myb mice; and the Transgenic/Gene Knockout Shared Resource for technical assistance. This work was supported by a grant from the NIH and from the National Cancer Institute Cancer Center Support (CORE) program, and by the American Lebanese Syrian Associated Charities of St Jude Children's Research Hospital.

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Authors and Affiliations

  1. Department of Biochemistry, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee, 38105, USA
    Lawryn H. Kasper, Fayçal Boussouar, Paul A. Ney & Paul K. Brindle
  2. Division of Experimental Hematology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee, 38105, USA
    Carl W. Jackson
  3. Department of Pathology, St Jude Children's Research Hospital, 332 North Lauderdale, Memphis, Tennessee, 38105, USA
    Jerold Rehg
  4. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota, 55905, USA
    Jan M. van Deursen

Authors

  1. Lawryn H. Kasper
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  2. Fayçal Boussouar
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  3. Paul A. Ney
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  4. Carl W. Jackson
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  5. Jerold Rehg
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  6. Jan M. van Deursen
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  7. Paul K. Brindle
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Correspondence toPaul K. Brindle.

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Kasper, L., Boussouar, F., Ney, P. et al. A transcription-factor-binding surface of coactivator p300 is required for haematopoiesis.Nature 419, 738–743 (2002). https://doi.org/10.1038/nature01062

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