Involvement of JNK in the regulation of autophagic cell death

• Published in: Oncogene Vol. 29; no. 14; pp. 2070 - 2082
• Main Authors: Shimizu, S, Konishi, A, Nishida, Y, Mizuta, T, Nishina, H, Yamamoto, A, Tsujimoto, Y
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.04.2010; Nature Publishing Group
• Subjects: 631/45/607/275; 631/80/82/39; Ageing, cell death; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Autophagy - physiology; Base Sequence; BAX protein; bcl-2 Homologous Antagonist-Killer Protein - deficiency; bcl-2 Homologous Antagonist-Killer Protein - genetics; Bcl-2 protein; bcl-2-Associated X Protein - deficiency; bcl-2-Associated X Protein - genetics; bcl-X Protein - metabolism; Biological and medical sciences; c-Jun N-terminal kinases; Cell activation; Cell Biology; Cell death; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Embryo fibroblasts; Enzyme Activation; Etoposide; Etoposide - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Regulation; Gene Knockdown Techniques; Genetic regulation; HeLa Cells; Human Genetics; Humans; Internal Medicine; JNK Mitogen-Activated Protein Kinases - metabolism; Kinases; Medicine; Medicine & Public Health; Metazoa; Mice; Mitochondria; Molecular and cellular biology; Oncology; original-article; Phosphorylation; Proteins; Staurosporine; Staurosporine - pharmacology; Japan; autophagic cell death; JNK; Atg5; Regulation(control); Cell death; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.487

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.