The effects of FBW7 ablation on nuclear receptor transcriptional regulation

The ligand-bound vitamin D receptor (VDR) recruits the E3 ligase FBW7 to enhance the proteasomal turnover of the DNA-bound transcription factor cMYC (2, 3). Unexpectedly, FBW7 functions as a cofactor of VDR trans-activation and is recruited to VDR target genes. Our goals are to understand the role of the E3 ligase FBW7 as a cofactor of transcriptional regulation using engineered cell lines responsive to multiple nuclear receptor ligands. In addition to its effects on VDR signaling, we recently found that ablation of FBW7 strongly compromises transactivation by related retinoic acid receptors (RARs) and by estrogen receptor alpha (ER alpha). We will extend these findings to analyze global effects of FBW7 ablation on hormone-regulated gene transcription and the ligand-dependent (and –independent), genome-wide recruitment of FBW7 to chromatin. These studies will establish the extent and mechanisms of action of FBW7 as a regulator of nuclear receptor- and non-nuclear receptor-regulated gene transcription.