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Molecular and Cellular Biology, September 1999, p. 6164-6173, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Multiple Signal Input and Output Domains of the 160-Kilodalton Nuclear Receptor Coactivator Proteins

Han Ma,1,2 Heng Hong,1,2 Shih-Ming Huang,1,2 Ryan A. Irvine,3,4 Paul Webb,5 Peter J. Kushner,5 Gerhard A. Coetzee,3,4 and Michael R. Stallcup1,2,*

1Departments of Pathology,2 Biochemistry and Molecular Biology,4 Urology, and 3Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California 90033, and 5Metabolic Research Unit, University of California at San Francisco, San Francisco, California 94143

Received 10 May 1999/Accepted 8 June 1999

Members of the 160-kDa nuclear receptor coactivator family (p160 coactivators) bind to the conserved AF-2 activation function found in the hormone binding domains of nuclear receptors (NR) and are potent transcriptional coactivators for NRs. Here we report that the C-terminal region of p160 coactivators glucocorticoid receptor interacting protein 1 (GRIP1), steroid receptor coactivator 1 (SRC-1a), and SRC-1e binds the N-terminal AF-1 activation function of the androgen receptor (AR), and p160 coactivators can thereby enhance transcriptional activation by AR. While they all interact efficiently with AR AF-1, these same coactivators have vastly different binding strengths with and coactivator effects on AR AF-2. p160 activation domain AD1, which binds secondary coactivators CREB binding protein (CBP) and p300, was previously implicated as the principal domain for transmitting the activating signal to the transcription machinery. We identified a new highly conserved motif in the AD1 region which is important for CBP/p300 binding. Deletion of AD1 only partially reduced p160 coactivator function, due to signaling through AD2, another activation domain located at the C-terminal end of p160 coactivators. C-terminal coactivator fragments lacking AD1 but containing AD2 and the AR AF-1 binding site served as efficient coactivators for full-length AR and AR AF-1. The two signal input domains (one that binds NR AF-2 domains and one that binds AF-1 domains of some but not all NRs) and the two signal output domains (AD1 and AD2) of p160 coactivators played different relative roles for two different NRs: AR and thyroid hormone receptor.

* Corresponding author. Mailing address: Department of Pathology, HMR 301, University of Southern California, 2011 Zonal Ave., Los Angeles, CA 90033. Phone: (323) 442-1289. Fax: (323) 442-3049. E-mail: stallcup{at}hsc.usc.edu.

Molecular and Cellular Biology, September 1999, p. 6164-6173, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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