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ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis
Author(s) -
Iriyama Takayuki,
Takeda Kohsuke,
Nakamura Hiromi,
Morimoto Yoshifumi,
Kuroiwa Takumi,
Mizukami Junya,
Umeda Tsuyoshi,
Noguchi Takuya,
Naguro Isao,
Nishitoh Hideki,
Saegusa Kaoru,
Tobiume Kei,
Homma Toshiki,
Shimada Yutaka,
Tsuda Hitoshi,
Aiko Satoshi,
Imoto Issei,
Inazawa Johji,
Chida Kazuhiro,
Kamei Yoshimasa,
Kozuma Shiro,
Taketani Yuji,
Matsuzawa Atsushi,
Ichijo Hidenori
Publication year - 2009
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.32
Subject(s) - carcinogenesis , biology , inflammation , ask1 , apoptosis , microbiology and biotechnology , cancer research , cytokine , signal transduction , mediator , immunology , cancer , genetics , mitogen activated protein kinase kinase , protein kinase c
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.