Document Detail

Response of SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) corepressors to mitogen-activated protein kinase kinase kinase cascades is determined by alternative mRNA splicing.
MedLine Citation:
PMID:  17519355     Owner:  NLM     Status:  MEDLINE    
The SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) corepressors are important mediators of transcriptional repression by nuclear hormone receptors. SMRT is regulated by MAPK kinase kinase (MAPKKK) cascades that induce its release from its receptor partners, its export from nucleus to cytoplasm, and derepression of target gene expression. Intriguingly, the otherwise closely related N-CoR is refractory to MAPKKK signaling under the same conditions. However, both SMRT and N-CoR are expressed as a series of alternatively spliced protein variants differing in structure and function. We have now characterized the impact of this alternative mRNA splicing on the corepressor response to MAPKKK signaling. Whereas the SMRTalpha, SMRTtau, and SMRTsp2 splice variants are released from their nuclear receptor partners in response to MAPKKK activation, the SMRTsp18 variant, which resembles N-CoR in its overall molecular architecture, is relatively refractory to this kinase-induced release. Alternative splicing of N-CoR, in contrast, had only minimal effects on the resistance of this corepressor to MAPKKK inhibition. Notably, all of the SMRT splice variants examined redistributed from nucleus to cytoplasm in response to MAPKKK cascade signaling, but none of the N-CoR splice variants did so. Different tiers of the MAPKKK cascade hierarchy contributed to these different aspects of corepressor regulation, with MAP/ERK kinase kinase 1 and MAP/ERK kinase 1 regulating subcellular redistribution and ERK2 regulating nuclear receptor-corepressor interaction. We conclude that cells can customize their transcriptional response to MAPKKK cascade signaling by selective expression of the SMRT or N-CoR locus, by selective utilization of a specific corepressor splice variant, and by selective exploitation of specific tiers of the MAPK cascade.
Brian A Jonas; Natalia Varlakhanova; Fumihiko Hayakawa; Michael Goodson; Martin L Privalsky
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-05-22
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  21     ISSN:  0888-8809     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2007 Aug 
Date Detail:
Created Date:  2007-07-26     Completed Date:  2007-09-28     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1924-39     Citation Subset:  IM    
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MeSH Terms
Alternative Splicing / physiology*
Cell Line
Cercopithecus aethiops
DNA-Binding Proteins / genetics,  metabolism*
MAP Kinase Kinase Kinases / physiology*
MAP Kinase Signaling System / physiology*
Nuclear Proteins / genetics,  metabolism*
Nuclear Receptor Co-Repressor 1
Nuclear Receptor Co-Repressor 2
Protein Isoforms / genetics,  metabolism
RNA, Messenger / genetics,  metabolism*
Repressor Proteins / genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Nuclear Receptor Co-Repressor 1; 0/Nuclear Receptor Co-Repressor 2; 0/Protein Isoforms; 0/RNA, Messenger; 0/Repressor Proteins; EC Kinase Kinase Kinases

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