Involvement of JNK in the regulation of autophagic cell death.
Programmed cell death is a crucial process in the normal development and physiology of metazoans, and it can be divided into several categories that include type I death (apoptosis) and type II death (autophagic cell death). The Bcl-2 family proteins are well-characterized regulators of apoptosis, among which multidomain pro-apoptotic members (such as Bax and Bak) function as a mitochondrial gateway at which various apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double-knockout (DKO) mice are resistant to apoptosis, we have previously reported that these cells still die by autophagy in response to various death stimuli. In this study, we found that jun N-terminal kinase (JNK) was activated in etoposide- and staurosporine-treated, but not serum-starved, Bax/Bak DKO cells, and that autophagic cell death was suppressed by the addition of a JNK inhibitor and by a dominant-negative mutant of JNK. Studies with sek1(-/-)mkk7(-/-) cells revealed that disruption of JNK prevented the induction of autophagic cell death. Co-activation of JNK and autophagy induced autophagic cell death. Activation of JNK occurred downstream of the induction of autophagy, and was dependent on the autophagic process. These results indicate that JNK activation is crucial for the autophagic death of Bax/Bak DKO cells.
Shimizu
S
S
Department of Medical Genetics, Osaka University Medical School,Yamada-oka, Suita, Osaka, Japan. shimizu.pcb@mri.tmd.ac.jp
Konishi
A
A
Nishida
Y
Y
Mizuta
T
T
Nishina
H
H
Yamamoto
A
A
Tsujimoto
Y
Y
D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001483:Base Sequence; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D019311:Staurosporine / Q000494:pharmacology; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics; D051020:bcl-X Protein / Q000378:metabolism
D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D005047:Etoposide; D048031:JNK Mitogen-Activated Protein Kinases; D019311:Staurosporine