TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.

A key strategy to achieve regulated gene expression in higher eukaryotes is to prevent illegitimate signal-independent activation by imposing robust control on the dismissal of corepressors. Here, we report that many signaling pathways, including Notch, NF-kappaB, and nuclear receptor ligands, are subjected to a dual-repression "checkpoint" based on distinct corepressor ...
complexes. Gene activation requires the release of both CtBP1/2- and NCoR/SMRT-dependent repression, through the coordinate action of two highly related exchange factors, the transducer beta-like proteins TBL1 and TBLR1, that license ubiquitylation and degradation of CtBP1/2 and NCoR/SMRT, respectively. Intriguingly, their function and differential specificity reside in only five specific Ser/Thr phosphorylation site differences, regulated by direct phosphorylation at the level of the promoter, as exemplified by the role of PKCdelta in TBLR1-dependent dismissal of NCoR. Thus, our data reveal a strategy of dual-factor repression checkpoints, in which dedicated exchange factors serve as sensors for signal-specific dismissal of distinct corepressors, with specificity imposed by upstream signaling pathways.
Mesh Terms:
Alcohol Oxidoreductases, Animals, Breast Neoplasms, Cell Line, Cell Line, Tumor, DNA-Binding Proteins, Female, Gene Expression Regulation, Neoplastic, Genes, Reporter, Humans, Nuclear Proteins, Nuclear Receptor Co-Repressor 2, Promoter Regions, Genetic, Proteasome Endopeptidase Complex, Receptors, Cytoplasmic and Nuclear, Repressor Proteins, Transcription, Genetic, Transcriptional Activation, Transducin, Ubiquitin
Mol. Cell
Date: Mar. 28, 2008
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