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Molecular and Cellular Biology, November 2001, p. 7509-7522, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7509-7522.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The HOX Homeodomain Proteins Block CBP Histone Acetyltransferase Activity

Wei-fang Shen,1,* Keerthi Krishnan,1 H. J. Lawrence,1 and Corey Largman1,2

Departments of Medicine1 and Dermatology,2 VA Medical Center and University of California, San Francisco, California

Received 29 May 2001/Returned for modification 22 June 2001/Accepted 20 July 2001

Despite the identification of PBC proteins as cofactors that provide DNA affinity and binding specificity for the HOX homeodomain proteins, HOX proteins do not demonstrate robust activity in transient-transcription assays and few authentic downstream targets have been identified for these putative transcription factors. During a search for additional cofactors, we established that each of the 14 HOX proteins tested, from 11 separate paralog groups, binds to CBP or p300. All six isolated homeodomain fragments tested bind to CBP, suggesting that the homeodomain is a common site of interaction. Surprisingly, CBP-p300 does not form DNA binding complexes with the HOX proteins but instead prevents their binding to DNA. The HOX proteins are not substrates for CBP histone acetyltransferase (HAT) but instead inhibit the activity of CBP in both in vitro and in vivo systems. These mutually inhibitory interactions are reflected by the inability of CBP to potentiate the low levels of gene activation induced by HOX proteins in a range of reporter assays. We propose two models for HOX protein function: (i) HOX proteins may function without CBP HAT to regulate transcription as cooperative DNA binding molecules with PBX, MEIS, or other cofactors, and (ii) the HOX proteins may inhibit CBP HAT activity and thus function as repressors of gene transcription.

* Corresponding author. Mailing address: VA Medical Center, 4150 Clement St., San Francisco, CA 94121. Phone: (415) 221-4810, ext. 3427. Fax: (415) 221-4262. E-mail: wfshen{at}itsa.ucsf.edu.

Molecular and Cellular Biology, November 2001, p. 7509-7522, Vol. 21, No. 21
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.21.7509-7522.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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