Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent trans-repression of activator protein-1

Mol Endocrinol. 2008 Aug;22(8):1767-80. doi: 10.1210/me.2007-0574. Epub 2008 Jun 5.


The term activator protein (AP)-1 describes homodimeric and heterodimeric transcription factors composed of members of the Jun, Fos, and cAMP response element-binding protein (CREB)/activating transcription factor (ATF) families of proteins. Distinct AP-1 dimers, for instance the prototypical c-Jun:c-Fos and c-Jun:ATF2 dimers, are differentially regulated by signaling pathways and bind related yet distinct response elements in the regulatory regions of AP-1 target genes. Little is known about the dimer-specific regulation of AP-1 activity at the promoter of its target genes. We have previously shown that nTrip6, the nuclear isoform of the LIM domain protein Trip6, acts as an AP-1 coactivator. Moreover, nTrip6 is an essential component of glucocorticoid receptor (GR)-mediated trans-repression of AP-1, in that it mediates the tethering of GR to the promoter-bound AP-1. We have now discovered a striking specificity of nTrip6 actions determined by the binding preference of its LIM domains. We show that nTrip6 interacts only with Fos family members. Consequently, nTrip6 is a selective coactivator for AP-1 dimers containing Fos. nTrip6 also assembles activated GR to c-Jun:c-Fos-driven promoters. Neither nTrip6 nor GR are recruited to a promoter occupied by c-Jun:ATF2. Thus, only Fos-containing dimers are trans-repressed by GR. Thus, the dimer composition of AP-1 determines the mechanism of both the positive and negative regulation of AP-1 transcriptional activity. Interestingly, on a second level of action, GR represses the increase in transcriptional activity of c-Jun:ATF2 induced by c-Jun N-terminal kinase (JNK)-dependent phosphorylation. This repression depends on GR-mediated induction of MAPK phosphatase 1 (MKP-1) expression, which results in c-Jun N-terminal kinase inactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities
  • Activating Transcription Factor 2 / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Dimerization
  • Dual Specificity Phosphatase 1 / biosynthesis
  • Enzyme Activation / radiation effects
  • Enzyme Induction / radiation effects
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • LIM Domain Proteins
  • Mice
  • Promoter Regions, Genetic / genetics
  • Proteasome Endopeptidase Complex
  • Protein Binding / radiation effects
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Receptors, Glucocorticoid / metabolism*
  • Repressor Proteins / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / metabolism*
  • Transcriptional Activation / genetics
  • Transcriptional Activation / radiation effects
  • Ultraviolet Rays


  • Activating Transcription Factor 2
  • Adaptor Proteins, Signal Transducing
  • LIM Domain Proteins
  • PSMC5 protein, human
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Receptors, Glucocorticoid
  • Repressor Proteins
  • Transcription Factor AP-1
  • Transcription Factors
  • JNK Mitogen-Activated Protein Kinases
  • Dual Specificity Phosphatase 1
  • Dusp1 protein, mouse
  • Proteasome Endopeptidase Complex
  • ATPases Associated with Diverse Cellular Activities