Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator

Thyroid hormone receptor-binding protein, an LXXLL motif-containing protein, functions as a general coactivator

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Edited by Michael G. Rosenfeld, University of California at San Diego, La Jolla, CA, and approved March 15, 2000 (received for review December 20, 1999)

Abstract

Nuclear hormone receptors activate gene transcription through ligand-dependent association with coactivators. Specific LXXLL sequence motifs present in these cofactors are sufficient to mediate these ligand-induced interactions. A thyroid hormone receptor (TR)-binding protein (TRBP) was cloned by a Sos-Ras yeast two-hybrid system using TRβ1-ligand binding domain as bait. TRBP contains 2063 amino acid residues, associates with TR through a LXXLL motif, and is ubiquitously expressed in a variety of tissues and cells. TRBP strongly transactivates through TRβ1 and estrogen receptor in a dose-related and ligand-dependent manner, and also exhibits coactivation through AP-1, CRE, and NFκB-response elements, similar to the general coactivator CBP/p300. The C terminus of TRBP binds to CBP/p300 and DRIP130, a component of the DRIP/TRAP/ARC complex, which suggests that TRBP may activate transcription by means of such interactions. Further, the association of TRBP with the DNA-dependent protein kinase (DNA-PK) complex and DNA-independent phosphorylation of TRBP C terminus by DNA-PK point to a potential connection between transcriptional control and chromatin architecture regulation.

Footnotes

↵ * Present address: Eli Lilly and Company, Lilly Corporate Center, DC 0424, Indianapolis, IN 46285.
↵ † To whom reprint requests should be sent at present address. E-mail: chin{at}lilly.com.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF171667 for full-length human TRBP and AF176351 for partial rat TRBP).
Abbreviations:

LBD,

ligand-binding domain;

DBD,

DNA-binding domain;

TR,

thyroid hormone receptor;

TRBP,

TR-binding protein;

TRE,

thyroid hormone-response element;

DNA-PK,

DNA-dependent protein kinase;

DRIP,

vitamin D receptor-interacting protein;

SRC-1,

steroid receptor coactivator 1;

CBP,

CREB-binding protein;

PKA,

protein kinase A;

MEKK,

MEK kinase;

Triac,

3,3′,5-triiodothyroacetic acid;

T3,

3,3′,5-triiodo-l-thyronine;

GST,

glutathione S-transferase;

HAT,

histone acetyltransferase