The hormone estrogen directly stimulates gene expression through activation of its corresponding nuclear receptors. Frasor et al. propose that one such estrogen target gene encodes Siah2, a ubiquitin ligase, which propagates a signal that feeds back to further enhance estrogen-dependent gene transcription. In breast cancer cell lines, estrogen treatment enhanced expression of Siah2. Ubiquitin ligases can mark target proteins for degradation by the proteasome, and one of Siah2's targets is N-CoR, a repressor of nuclear receptor-dependent transcription. Loss of the N-CoR protein in estrogen-treated cells was blocked by proteasome inhibitors. Furthermore, inhibition of expression of Siah2 with siRNA prevented the effect of estrogen to decrease abundance of N-CoR and to enhance transcription of vitamin D3 24-hydroxylase, a gene repressed by N-CoR. The authors propose that regulation of N-CoR may feed back not only transcriptional regulation by estrogen but also on the broader set of genes whose expression is repressed by N-CoR.
J. Frasor, J. M. Danes, C. C. Funk, B. S. Katzenellenbogen, Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes. Proc. Natl. Acad. Sci. U.S.A. 102, 13153-13157 (2005). [Abstract] [Full Text]