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

Mol Cell. 2008 Mar 28;29(6):755-66. doi: 10.1016/j.molcel.2008.01.020.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Oxidoreductases / genetics*
  • Animals
  • Breast Neoplasms
  • Cell Line
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Co-Repressor 2
  • Promoter Regions, Genetic*
  • Proteasome Endopeptidase Complex / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation
  • Transducin / metabolism*
  • Ubiquitin / metabolism

Substances

  • DNA-Binding Proteins
  • NCOR2 protein, human
  • Ncor2 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • TBL1X protein, human
  • TBL1XR1 protein, human
  • Tbl1x protein, mouse
  • Ubiquitin
  • Alcohol Oxidoreductases
  • C-terminal binding protein
  • Proteasome Endopeptidase Complex
  • Transducin

Grant support