Forkhead homologue in rhabdomyosarcoma functions as a bifunctional nuclearreceptor-interacting protein with both coactivator and corepressor functions

In a search for novel transcriptional intermediary factors for the estrogen receptor (ER), we used the ligand-binding domain and hinge region of ER as bait in a yeast two-hybrid screen of a cDNA library derived from tamoxifen -resistant MCF-7 human breast tumors from an in vivo athymic nude mouse mod el. Here we report the isolation and characterization of the forkhead homol ogue in rhabdomyosarcoma (FKHR), a recently described member of the hepatoc yte nuclear factor 3/forkhead homeotic gene family, as a nuclear hormone re ceptor (NR) intermediary protein. FKHR interacts with both steroid and nons teroid NRs, although the effect of ligand on this interaction varies by rec eptor type. The interaction of FKHR with ER is enhanced by estrogen, wherea s its interaction with thyroid hormone receptor and retinoic acid receptor is ligand-independent. In addition, FKHR differentially regulates the trans activation mediated by different NRs. Transient transfection of FKHR into m ammalian cells dramatically represses transcription mediated by the ER, glu cocorticoid receptor, and progesterone receptor. In contrast, FKHR stimulat es rather than represses retinoic acid receptor- and thyroid hormone recept or-mediated transactivation. Most intriguingly, overexpression of FKHR dram atically inhibits the proliferation of ER-dependent MCF-7 breast cancer cel ls. Therefore, FKHR represents a bifunctional NR intermediary protein that can act as either a coactivator or corepressor, depending on the receptor t ype.