Evidence for a role of the JNK cascade in Smad7-mediated apoptosis.
Smad proteins are central mediators of the transcriptional effects of transforming growth factor beta (TGF-beta) superfamily that regulate a wide variety of biological processes. Smad7, an inhibitory Smad protein that prevents TGF-beta signaling by interacting with the activated type I TGF-beta receptor, was recently shown to induce sensitization of cells to different forms of cell death. Here we examined the effect of Smad7 on the c-Jun N-terminal kinase (JNK) cascade and investigated the role of this cascade in both the inhibitory and apoptotic functions of Smad7. The transient and stable expression of Smad7 caused a strong and sustained activation of JNK. Expression of a dominant-interfering mutant of mitogen-activated protein kinase kinase 4, which completely abolished Smad7-induced activation of JNK, had no effect on Smad7-mediated inhibition of TGF-beta signaling, indicating that the inhibitory function of Smad7 is independent of the JNK cascade. In contrast, expression of the dominant-interfering mutant of mitogen-activated protein kinase kinase 4 impaired the ability of Smad7 to promote cell death. These experiments reveal a novel link between Smad7 and the JNK cascade, which is essential for potentiation of cell death by this inhibitory Smad.
Mazars
A
A
INSERM U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571 Paris, Cedex 12, France.
Lallemand
F
F
Prunier
C
C
Marais
J
J
Ferrand
N
N
Pessah
M
M
Cherqui
G
G
Atfi
A
A
D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002460:Cell Line; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D051906:Smad7 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases