c-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity

• Published in: The Journal of biological chemistry 2000-09, Vol.275 (37), p.28858-28865
• Main Authors: Dennler, S, Prunier, C, Ferrand, N, Gauthier, J M, Atfi, A
• Format: Article
• Language: English
• Subjects: Animals; c-Jun protein; Cell Nucleus - metabolism; COS Cells; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - physiology; Humans; MAP Kinase Kinase 1; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases - physiology; Protein-Serine-Threonine Kinases - physiology; Proto-Oncogene Proteins c-jun - physiology; Smad3 Protein; Trans-Activators - antagonists & inhibitors; Trans-Activators - physiology; Transcription, Genetic; Transforming Growth Factor beta - physiology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M910358199

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.