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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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