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.

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