title: E1A and a nuclear receptor corepressor splice variant (N-CoRI) are thyroid hormone receptor coactivators that bind in the corepressor mode.
abstract: Unliganded thyroid hormone (TH) receptors (TRs) and other nuclear receptors (NRs) repress transcription of hormone-activated genes by recruiting corepressors (CoRs), such as NR CoR (N-CoR) and SMRT. Unliganded TRs also activate transcription of TH-repressed genes. Some evidence suggests that these effects also involve TR/CoR contacts; however, the precise reasons that CoRs activate transcription in these contexts are obscure. Unraveling these mechanisms is complicated by the fact that it is difficult to decipher direct vs. indirect effects of TR-coregulator contacts in mammalian cells. In this study, we used yeast, Saccharomyces cerevisiae, which lack endogenous NRs and NR coregulators, to determine how unliganded TRs can activate transcription. We previously showed that adenovirus 5 early-region 1A coactivates unliganded TRs in yeast, and that these effects are blocked by TH. We show here that human adenovirus type 5 early region 1A (E1A) contains a short peptide (LDQLIEEVL amino acids 20-28) that resembles CoR-NR interaction motifs (CoRNR boxes), and that this motif is required for TR binding and coactivation. Although full-length N-CoR does not coactivate TR in yeast, a naturally occurring N-CoR variant (N-CoR(I)) and an artificial N-CoR truncation (N-CoR(C)) that retain CoRNR boxes but lack N-terminal repressor domains behave as potent and direct TH-repressed coactivators for unliganded TRs. We conclude that E1A and N-CoR(I) are naturally occurring TR coactivators that bind in the typical CoR mode and suggest that similar factors could mediate transcriptional activation by unliganded TRs in mammals.
authors.affiliation: Department of Medicine, Endocrine Division, Mount Sinai Hospital, University of Toronto Medical School, Toronto, ON, Canada M5G 1X5.
authors.forename: Xianwang
authors.initials: X
authors.lastname: Meng
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
authors.forename: Yong-Fan
authors.initials: YF
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Shuen
authors.forename: Ahmed F
authors.initials: AF
authors.lastname: Yousef
authors.forename: John D
authors.initials: JD
authors.lastname: Baxter
authors.forename: Joe S
authors.initials: JS
authors.lastname: Mymryk
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
mesh_terms: D017500:Adenovirus E1A Proteins / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D005982:Glutathione Transferase; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques
chemical_list: D017500:Adenovirus E1A Proteins; C539127:NCOR1 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D005982:Glutathione Transferase