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Identification of Mouse TRAP100: a Transcriptional Coregulatory Factor for Thyroid Hormone and Vitamin D Receptors

Department of Physiology University of Maryland School of Medicine Baltimore, Maryland 21201

Nuclear hormone receptors (NRs) regulate transcription in part by recruiting distinct transcriptional coregulatory complexes to target gene promoters. The thyroid hormone receptor (TR) was recently purified from thyroid hormone-cultured HeLa cells in association with a complex of novel nuclear proteins termed TRAPs (thyroid hormone receptor-associated proteins) ranging in size from 20 to 240 kDa. The TRAP complex markedly enhances TR-mediated transcription in vitro, suggesting a coactivator role for one or more of the TRAP components. Here we present the mouse cDNA for the 100-kDa component of the TRAP complex (mTRAP100). The mTRAP100 protein contains seven LxxLL motifs thought to be potential binding surfaces for liganded NRs, yet surprisingly fails to interact with TR and other NRs in vitro. By contrast, mTRAP100 coprecipitates in vivo with another component of the TRAP complex (TRAP220), which directly contacts TR and the vitamin D receptor in a ligand-dependent manner. Our findings thus suggest that TRAP100 is targeted to NRs in association with TRAP complexes specifically containing TRAP220. Transient overexpression of mTRAP100 in mammalian cells further enhances ligand-dependent transcription by both TR and the vitamin D receptor, revealing a functional role for mTRAP100 in NR-mediated transactivation. The presence of an intrinsic mTRAP100 transactivation function is suggested by the ability of mTRAP100 to activate transcription constituitively when tethered to the GAL4 DNA-binding domain. Collectively, these findings suggest that TRAP100, in concert with other TRAPs, plays an important functional role in mediating transactivation by specific NRs.

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