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.
Perissi
Valentina
V
Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Scafoglio
Claudio
C
Zhang
Jie
J
Ohgi
Kenneth A
KA
Rose
David W
DW
Glass
Christopher K
CK
Rosenfeld
Michael G
MG
D000429:Alcohol Oxidoreductases / Q000235:genetics*; D000818:Animals; D001943:Breast Neoplasms; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D056985:Nuclear Receptor Co-Repressor 2; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015293:Transducin / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D004268:DNA-Binding Proteins; C539130:NCOR2 protein, human; C539131:Ncor2 protein, mouse; D009687:Nuclear Proteins; D056985:Nuclear Receptor Co-Repressor 2; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; C485613:Tbl1x protein, mouse; D025801:Ubiquitin; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D046988:Proteasome Endopeptidase Complex; D015293:Transducin