Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis.
The c-Jun N-terminal kinases (JNKs) are activated by a variety of stress inducing agents and are thought to regulate apoptosis in a cell type and signal-specific manner. We have used fibroblasts lacking JNK1 or JNK2 to define their roles in response to different stress signals. Lack of JNK1 results in reduced c-Jun phosphorylation and resistance to UV-induced cell death. JNK2 deficient cells show increased sensitivity to UV irradiation which correlates with elevated and sustained phosphorylation of JNK1 and c-Jun. On the contrary, both Jnk1-/- and Jnk2-/- cells were more sensitive to tumor necrosis factor - alpha (TNF-alpha) and sorbitol-induced cell death. Treatment of Jnk1-/- cells with these reagents resulted in reduced JNK activity and a concomitant reduction of c-Jun phosphorylation, suggesting that phosphorylation of c-Jun does not influence TNF-alpha and sorbitol-induced apoptosis in fibroblasts. Moreover, both JNK1 and JNK2 appear to negatively regulate apoptosis independent of c-Jun phosphorylation. These data provide genetic evidence that although the JNK pathway is activated by a plethora of signals, it is required only for the induction of UV-induced cell death in a c-Jun phosphorylation-dependent manner, but not for TNF-alpha and sorbitol-induced apoptosis.
Hochedlinger
Konrad
K
Research Institute of Molecular Pathology (IMP), Dr. Bohrgasse 7, A-1030 Vienna, Austria.
Wagner
Erwin F
EF
Sabapathy
Kanaga
K
D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D017353:Gene Deletion; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D013012:Sorbitol / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014466:Ultraviolet Rays
D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha; D013012:Sorbitol; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases