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

EMBO J. 2009 Apr 8;28(7):843-53. doi: 10.1038/emboj.2009.32.

Takayuki Iriyama ¹, 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 Kamei, Shiro Kozuma, Yuji Taketani, Atsushi Matsuzawa, Hidenori Ichijo

Affiliations

Affiliation

1 Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

PMID: 19214184 DOI: 10.1038/emboj.2009.32

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.

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