c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.
Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine that exerts its effects through a heteromeric complex of transmembrane serine/threonine kinase receptors. At least two intracellular pathways are activated by TGF-beta as follows: the SAPK/JNK, involving the MEKK1, MKK4, and JNK cascade, and the Smad pathway. Here, we report that the SAPK/JNK pathway inhibits the Smad3 pathway. Expression of dominant negative or constitutively active mutants of kinases of the SAPK/JNK pathway, respectively, activates or represses a TGF-beta-induced reporter containing Smad3-binding sites. This effect is not dependent on blocking of Smad3 nuclear translocation but involves a functional interaction between Smad3 and c-Jun, a transcription factor activated by the SAPK/JNK pathway. Overexpression of constitutively active MEKK1 or MKK4 mutants stabilizes the physical interaction between Smad3 and c-Jun, whereas dominant negative mutants inhibit this interaction. Moreover, overexpression of wild-type c-Jun inhibits Smad3-dependent transcription. However, c-Jun does not inhibit Smad3 binding to DNA in vitro. The repression obtained with a c-Jun mutant unable to activate transcription through AP-1 sites indicates that the inhibitory mechanism does not rely on the induction of a Smad3 repressor by c-Jun, suggesting that c-Jun could act as a Smad3 co-repressor. The inhibition of the Smad3 pathway by the SAPK/JNK pathway, both triggered by TGF-beta, could participate in a negative feedback loop to control TGF-beta responses.
Dennler
S
S
Laboratoire GlaxoWellcome, 25 Avenue du Québec, 91951 Les Ulis Cedex and INSERM U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France.
Prunier
C
C
Ferrand
N
N
Gauthier
J M
JM
Atfi
A
A
D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases