Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor-dependent trans-repression of activator protein-1.
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.
Institut für Toxikologie und Genetik, Forschungszentrum Karlsruhe, Hermann-von-Helmholtz Platz 1, D- 76344 Eggenstein-Leopoldshafen, Germany.
Markus
M
Diefenbacher
Sylwia
S
Sekula
Christine
C
Heilbock
Jana V
JV
Maier
Margarethe
M
Litfin
Hans
H
van Dam
Marc
M
Castellazzi
Peter
P
Herrlich
Olivier
O
Kassel
D000074183:ATPases Associated with Diverse Cellular Activities; D051698:Activating Transcription Factor 2 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D019281:Dimerization; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis; D004789:Enzyme Activation / Q000528:radiation effects; D004790:Enzyme Induction / Q000528:radiation effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D060588:LIM Domain Proteins; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding / Q000528:radiation effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics / Q000528:radiation effects; D014466:Ultraviolet Rays
D051698:Activating Transcription Factor 2; D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C092282:PSMC5 protein, human; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D048031:JNK Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities