Abstract
Corepressors are large proteins that facilitate transcriptional repression through recruitment of histone-modifying enzymes. Two major corepressors, SMRT (silencing mediator for retinoid and thyroid hormone receptors) and N-CoR (nuclear receptor corepressor), have been shown to mediate repression associated with nuclear receptors and a myriad of other transcription factors. This review will focus on recent studies on these proteins, including newly discovered physiological roles of the corepressors, their modes of regulation, their roles in antiestrogen-resistant breast cancer and their functions during the cell cycle.
Highlights
Control of transcription is mediated by many signaling pathways, including small, non-protein steroids
The repression domains (RDs) likely serve as binding platforms for the various silencing enzymes recruited to repress gene promoters, including the histone deacetylases (HDACs)
We found that the cyclindependent kinase Cyclin-dependent kinase 2 (Cdk2) phosphorylates SMRT to generate Pin1 binding sites
Summary
Tamoxifen recruits corepressors SMRT and N-CoR to dimerized estrogen receptors [46] Binding of these corepressors to ERα results in repression of ERαtarget genes, including those involved in cell proliferation, through modification of histones and concomitant chromatin remodeling to a more compact state. Some breast cancers show ERα recruitment of coactivators even in the presence of tamoxifen, resulting in activation of proliferative genes Many of these tamoxifen-resistant breast cancers overexpress the oncogene ErbB2, which has been shown to increase coactivator levels and decrease corepressor levels, altering the delicate ratio between these critical factors. Suggest that inhibition of Cdk and/or Pin in ERα-positive and ErbB2-positive breast cancer cells will enhance the anti-tumor activity of tamoxifen.
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