ISOFORMS OF STEROID-RECEPTOR COACTIVATOR-1 DIFFER IN THEIR ABILITY TOPOTENTIATE TRANSCRIPTION BY THE ESTROGEN-RECEPTOR

Steroid receptor co-activator (SRC1) is one of a number of transcripti onal co-activators that are capable of potentiating the activity of nu clear receptors including the oestrogen receptor (ER), Here we report that two isoforms, SRC1a and SRC1e, which diverge at their C-termini, are functionally distinct as they differ in their abilities to enhance the activity of the ER in intact cells, SRC1e enhanced the ability of the ER to stimulate transcription to a greater extent than SRC1a, whi ch had negligible effects on certain promoters. To elucidate the basis of this functional difference, ve compared the nuclear receptor-bindi ng properties and mapped the transcriptional activation domains in the two SRC1 isoforms, Both isoforms share a triplet of nuclear receptor- binding moths (LXXLL moths) for binding to functional ER dimers, and a n activation domain which co-localizes with the CBP-binding domain, wh ile SRC1a contains a unique LXXLL moth in its C-terminus. Although thi s LXXLL motif increases the affinity for the ER in vitro, it does not appear to be responsible for the functional difference between the two isoforms, This difference is due to a second activation domain that i s CBP independent and is suppressed in the SRC1a isoform. Thus, SRC1 e xists as functionally distinct isoforms which are likely to play diffe rent roles in ER-mediated transcription.