ASK1 and ASK2 differentially regulate the counteracting roles of apoptosis and inflammation in tumorigenesis.
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.
Iriyama
Takayuki
T
Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Takeda
Kohsuke
K
Nakamura
Hiromi
H
Morimoto
Yoshifumi
Y
Kuroiwa
Takumi
T
Mizukami
Junya
J
Umeda
Tsuyoshi
T
Noguchi
Takuya
T
Naguro
Isao
I
Nishitoh
Hideki
H
Saegusa
Kaoru
K
Tobiume
Kei
K
Homma
Toshiki
T
Shimada
Yutaka
Y
Tsuda
Hitoshi
H
Aiko
Satoshi
S
Imoto
Issei
I
Inazawa
Johji
J
Chida
Kazuhiro
K
Kamei
Yoshimasa
Y
Kozuma
Shiro
S
Taketani
Yuji
Y
Matsuzawa
Atsushi
A
Ichijo
Hidenori
H
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000201:enzymology; D015603:Keratinocytes / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000276:immunology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D017382:Reactive Oxygen Species; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C116394:MAP kinase kinase kinase 6