Transcriptional intermediary factor 1α mediates physical interaction and functional synergy between the coactivator-associated arginine methyltransferase 1 and glucocorticoid receptor interacting protein 1 nuclear receptor coactivators

In previous studies transcriptional intermediary factor 1 alpha (TIF1 alpha) was identified as a direct binding partner and potential transcriptional coactivator for nuclear receptors (NRs) but its overexpression inhibited, rather than enhanced, transcriptional activation by NRs. Here we show that TIF1 alpha bound to and enhanced the function of the C- terminal activation domain ( AD) of coactivator associated arginine methyltransferase 1 ( CARM1) and the N- terminal AD of glucocorticoid receptor-interacting protein 1 (GRIP1). Furthermore, although TIF1 alpha had little or no NR coactivator activity by itself, it cooperated synergistically with GRIP1 and CARM1 to enhance NR-mediated transcription. Inhibition of endogenous TIF1 alpha expression reduced transcriptional activation by the GRIP1 N- terminal domain but not by the CARM1 C- terminal domain, suggesting that TIF1 alpha may be more important for mediating the activity of the former than the latter. Reduction of endogenous TIF1 alpha levels also compromised the androgen-dependent induction of an endogenous target gene of the androgen receptor. Finally, TIF1 alpha formed a ternary complex with the GRIP1N-terminal and CARM1 C- terminal domains. Thus, we conclude that TIF1 alpha cooperates with NR coactivators GRIP1 and CARM1 by forming a stable ternary complex with them and enhancing the AD function of one or both of them.