ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis

Takayuki Iriyama, Kohsuke Takeda, Hiromi Nakamura, Yoshifumi Morimoto, Takumi Kuroiwa, Junya Mizukami, Tsuyoshi Umeda, Takuya Noguchi, Isao Naguro, Hideki Nishitoh, Kaoru Saegusa, Kei Tobiume, Toshiki Homma, Yutaka Shimada, Hitoshi Tsuda, Satoshi Aiko, Issei Imoto, Johji Inazawa, Kazuhiro Chida, Yoshimasa KameiShiro Kozuma, Yuji Taketani, Atsushi Matsuzawa, Hidenori Ichijo

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Apoptosis and inflammation generally exert opposite effects on tumorigenesis: apoptosis serves as a barrier to tumour initiation, whereas inflammation promotes tumorigenesis. Although both events are induced by various common stressors, relatively little is known about the stress-induced signalling pathways regulating these events in tumorigenesis. Here, we show that stress-activated MAP3Ks, ASK1 and ASK2, which are involved in cellular responses to various stressors such as reactive oxygen species, differentially regulate the initiation and promotion of tumorigenesis. ASK2 in cooperation with ASK1 functioned as a tumour suppressor by exerting proapoptotic activity in epithelial cells, which was consistent with the reduction in ASK2 expression in human cancer cells and tissues. In contrast, ASK1-dependent cytokine production in inflammatory cells promoted tumorigenesis. Our findings suggest that ASK1 and ASK2 are critically involved in tumorigenesis by differentially regulating apoptosis and inflammation.

Original languageEnglish
Pages (from-to)843-853
Number of pages11
JournalEMBO Journal
Volume28
Issue number7
DOIs
Publication statusPublished - 2009 Apr 8

Keywords

  • ASK1
  • Apoptosis
  • Inflammation
  • MAP kinase
  • Reactive oxygen species

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Iriyama, T., Takeda, K., Nakamura, H., Morimoto, Y., Kuroiwa, T., Mizukami, J., Umeda, T., Noguchi, T., Naguro, I., Nishitoh, H., Saegusa, K., Tobiume, K., Homma, T., Shimada, Y., Tsuda, H., Aiko, S., Imoto, I., Inazawa, J., Chida, K., ... Ichijo, H. (2009). ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis. EMBO Journal, 28(7), 843-853. https://doi.org/10.1038/emboj.2009.32