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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Vo, N. K. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001)
Oike, Y. et al. Mice homozygous for a truncated form of CREB-binding protein exhibit defects in hematopoiesis and vasculo-angiogenesis. Blood 93, 2771–2779 (1999)
Yao, T. P. et al. Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell 93, 361–372 (1998)
Kung, A. L. et al. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 14, 272–277 (2000)
Gayther, S. A. et al. Mutations truncating the EP300 acetylase in human cancers. Nature Genet. 24, 300–303 (2000)
Goodman, R. H. & Smolik, S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 14, 1553–1577 (2000)
Parker, D. et al. Analysis of an activator:coactivator complex reveals an essential role for secondary structure in transcriptional activation. Mol. Cell 2, 353–359 (1998)
Parker, D. et al. Role of secondary structure in discrimination between constitutive and inducible activators. Mol. Cell. Biol. 19, 5601–5607 (1999)
Radhakrishnan, I. et al. Solution structure of the KIX domain of CBP bound to the transactivation domain of CREB: a model for activator:coactivator interactions. Cell 91, 741–752 (1997)
Jones, D. T. Protein secondary structure prediction based on position-specific scoring matrices. J. Mol. Biol. 292, 195–202 (1999)
Munoz, V. & Serrano, L. Elucidating the folding problem of helical peptides using empirical parameters. II. Helix macrodipole effects and rational modification of the helical content of natural peptides. J. Mol. Biol. 245, 275–296 (1995)
Kraus, W. L., Manning, E. T. & Kadonaga, J. T. Biochemical analysis of distinct activation functions in p300 that enhance transcription initiation with chromatin templates. Mol. Cell. Biol. 19, 8123–8135 (1999)
Yang, C., Shapiro, L. H., Rivera, M., Kumar, A. & Brindle, P. K. A role for CREB binding protein and p300 transcriptional coactivators in Ets-1 transactivation functions. Mol. Cell. Biol. 18, 2218–2229 (1998)
Jayaraman, G. et al. p300/cAMP-responsive element-binding protein interactions with ets-1 and ets-2 in the transcriptional activation of the human stromelysin promoter. J. Biol. Chem. 274, 17342–17352 (1999)
Mucenski, M. L. et al. A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65, 677–689 (1991)
Allen, R. D., Bender, T. P. & Siu, G. c-Myb is essential for early T cell development. Genes Dev. 13, 1073–1078 (1999)
Herschlag, D. & Johnson, F. B. Synergism in transcriptional activation: a kinetic view. Genes Dev. 7, 173–179 (1993)
Hartman, J. L., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001)
Jacobsson, S. et al. Flow cytometric analysis of megakaryocyte ploidy in chronic myeloproliferative disorders and reactive thrombocytosis. Eur. J. Haematol. 56, 287–292 (1996)
Jackson, C. W., Steward, S. A., Chenaille, P. J., Ashmun, R. A. & McDonald, T. P. An analysis of megakaryocytopoiesis in the C3H mouse: an animal model whose megakaryocytes have 32N as the modal DNA class. Blood 76, 690–696 (1990)
Sumner, R., Crawford, A., Mucenski, M. & Frampton, J. Initiation of adult myelopoiesis can occur in the absence of c-Myb whereas subsequent development is strictly dependent on the transcription factor. Oncogene 19, 3335–3342 (2000)
Rudolph, D. et al. Impaired fetal T cell development and perinatal lethality in mice lacking the cAMP response element binding protein. Proc. Natl Acad. Sci. USA 95, 4481–4486 (1998)
Arnold, J. T. et al. A single injection of pegylated murine megakaryocyte growth and development factor (MGDF) into mice is sufficient to produce a profound stimulation of megakaryocyte frequency, size, and ploidization. Blood 89, 823–833 (1997)
Kasper, L. H. et al. CREB binding protein interacts with nucleoporin-specific FG repeats that activate transcription and mediate NUP98-HOXA9 oncogenicity. Mol. Cell. Biol. 19, 764–776 (1999)
Shapiro, L. H. Myb and Ets proteins cooperate to transactivate an early myeloid gene. J. Biol. Chem. 270, 8763–8771 (1995)
Eckner, R. et al. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 8, 869–884 (1994)
Lecine, P., Blank, V. & Shivdasani, R. Characterization of the hematopoietic transcription factor NF-E2 in primary murine megakaryocytes. J. Biol. Chem. 273, 7572–7578 (1998)
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nature01062
This article is cited by
-
Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies
Signal Transduction and Targeted Therapy (2023)
-
The CBP KIX domain regulates long-term memory and circadian activity
BMC Biology (2020)
-
A novel cell-based screening assay for small-molecule MYB inhibitors identifies podophyllotoxins teniposide and etoposide as inhibitors of MYB activity
Scientific Reports (2018)
-
Peptidomimetic blockade of MYB in acute myeloid leukemia
Nature Communications (2018)
-
CBP/p300: intramolecular and intermolecular regulations
Frontiers in Biology (2018)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.