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Molecular and Cellular Biology, June 2002, p. 3729-3743, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3729-3743.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of CBP-Mediated Protein Acetylation by the Ets Family Oncoprotein PU.1

Wei Hong,1 Alexander Y. Kim,1 Sokun Ky,1 Carrie Rakowski,1 Sang-Beom Seo,2 Debabrata Chakravarti,2 Michael Atchison,3 and Gerd A. Blobel1,4*

Division of Hematology, Children's Hospital of Philadelphia,1 Department of Pharmacology,2 University of Pennsylvania School of Medicine,4 Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 191043

Received 11 December 2001/ Returned for modification 30 January 2002/ Accepted 28 February 2002

Aberrant expression of PU.1 inhibits erythroid cell differentiation and contributes to the formation of murine erythroleukemias (MEL). The molecular mechanism by which this occurs is poorly understood. Here we show that PU.1 specifically and efficiently inhibits CBP-mediated acetylation of several nuclear proteins, including the hematopoietic transcription factors GATA-1, NF-E2, and erythroid Krüppel-like factor. In addition, PU.1 blocks acetylation of histones and interferes with acetylation-dependent transcriptional events. CBP acetyltransferase activity increases during MEL cell differentiation as PU.1 levels decline and is inhibited by sustained PU.1 expression. Finally, PU.1 inhibits the differentiation-associated increase in histone acetylation at an erythroid-specific gene locus in vivo. Together, these findings suggest that aberrant expression of PU.1 and possibly other members of the Ets family of oncoproteins subverts normal cellular differentiation in part by inhibiting the acetylation of critical nuclear factors involved in balancing cellular proliferation and maturation.

* Corresponding author. Mailing address: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104. Phone: (215) 590-3988. Fax: (215) 590-4834. E-mail: blobel{at}email.chop.edu.

Molecular and Cellular Biology, June 2002, p. 3729-3743, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3729-3743.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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