SMRT and N-CoR are corepressor paralogs that play a critical role in mammalian development, reproduction, and homeostasis by partnering with and mediating transcriptional repression by a wide variety of metazoan transcription factors, including nuclear hormone receptors. Although encoded by distinct genetic loci, SMRT and N-CoR share substantial sequence interrelatedness and can form analogous assemblies with histone deacetylases and auxiliary factors, interact with similar sets of transcription factor partners, and exert overlapping functions. Notably, MAP kinase (MAPK) cascades operating downstream of growth factor and stress signaling pathways can phosphorylate SMRT, inducing its release from its transcription factor partners, export from nucleus to cytoplasm, and derepression of target gene expression. We previously reported that although SMRT is regulated by these MAPK cascades, the otherwise closely related N-CoR is not. Subsequently, it was demonstrated that SMRT and N-CoR are expressed as a series of alternatively spliced protein variants that differ in their structure and function. We therefore characterized the impact of these alternative mRNA splicing events on the corepressor response to MAPK signaling. Whereas the SMRTa, SMRTt, and SMRTsp2 splice variants are released from their nuclear receptor partners in response to MAPK activation, the SMRTsp18 variant, which resembles N-CoR in its overall molecular architecture, is largely refractory to this kinase-induced release. Alternative splicing of N-CoR, in contrast, had only minimal effects on the resistance of this corepressor to MAPK inhibition. In addition, whereas all of the SMRT splice variants examined redistributed from the nucleus to cytoplasm in response to MAPK cascade signaling, none of the N-CoR splice variants did so. Different tiers of the MAPK cascade hierarchy contributed to these aspects of corepressor regulation, with MEKK1 and MEK1 regulating subcellular redistribution and ERK2 regulating nuclear receptor-corepressor interaction. We conclude that cells can customize their transcriptional response to MAPK cascade signaling by selective expression of the SMRT or N-CoR locus, utilization of specific corepressor splice variants, and exploitation of specific MAPK cascade tiers.
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