Differential Regulation of Nuclear Corepressors, Silencing Mediator of Retinoic Acid and Thyroid Hormone Receptors and Nuclear Hormone Receptor Corepressor, by Kinase Signaling and Alternative MRNA Splicing

Previously, our laboratory reported that MAP kinase (MAPK) pathway signaling leads to the phosphorylation of SMRT and its dissociation from receptor partners, redistribution to the cytoplasm, and de-repression of its target genes. It has also been demonstrated that, through alternative splicing, multiple isoforms of SMRT and N-CoR are expressed. The work presented in this dissertation demonstrates that SMRT and N-CoR are differentially regulated by MAPK pathways and that alternative splicing further adds to the complexity of corepressor regulation. In particular, N-CoR is relatively refractory to MAPK signaling and is less extensively diversified by alternative splicing. SMRT, on the other hand, is generally susceptible to MAPK signaling and is subject to extensive alternative mRNA splicing events, leading to multiple isoforms with distinct NHR binding properties and sensitivities to MAPK signaling. These different forms of regulation generate several possible mechanisms for cells to customize transcriptional regulation through the differential expression of NHRs, corepressors, and signaling pathways.