Nuclear receptors (NRs) act as ligand‐inducible transcription factors which regulate the expression of target genes upon binding to cognate response elements. The ligand‐dependent activity of the NR activation function AF‐2 is believed to be mediated to the transcription machinery through transcriptional mediators/intermediary factors (TIFs). We report here the cloning of the 160 kDa human nuclear protein TIF2, which exhibits all properties expected for a mediator of AF‐2: (i) it interacts in vivo with NRs in an agonist‐dependent manner; (ii) it binds directly to the ligand‐binding domains (LBDs) of NRs in an agonist‐ and AF‐2‐integrity‐dependent manner in vitro; (iii) it harbours an autonomous transcriptional activation function; (iv) it relieves nuclear receptor autosquelching; and (v) it enhances the activity of some nuclear receptor AF‐2s when overexpressed in mammalian cells. TIF2 exhibits partial sequence homology with the recently isolated steroid receptor coactivator SRC‐1, indicating the existence of a novel gene family of nuclear receptor transcriptional mediators.
Nuclear receptors (NRs) bound to response elements mediate the effects of cognate ligands on gene expression. Their ligand‐dependent activation function, AF‐2, presumably acts on the basal transcription machinery through intermediary proteins/mediators. We have isolated a mouse nuclear protein, TIF1, which enhances RXR and RAR AF‐2 in yeast and interacts in a ligand‐dependent manner with several NRs in yeast and mammalian cells, as well as in vitro. Remarkably, these interactions require the amino acids constituting the AF‐2 activating domain conserved in all active NRs. Moreover, the oestrogen receptor (ER) AF‐2 antagonist hydroxytamoxifen cannot promote ER‐TIF1 interaction. We propose that TIF1, which contains several conserved domains found in transcriptional regulatory proteins, is a mediator of ligand‐dependent AF‐2. Interestingly, the TIF1 N‐terminal moiety is fused to B‐raf in the mouse oncoprotein T18.
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