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

Iriyama, Takayuki; Takeda, Kohsuke; Nakamura, Hiromi; Morimoto, Yuuki; Kuroiwa, Takumi; Mizukami, Junya; Umeda, Tomohiro; 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

doi:10.1038/emboj.2009.32

Cited by 120 publications

(118 citation statements)

References 39 publications

(60 reference statements)

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“…Indeed, several in vivo analyses revealed that ASK1 is a critical regulator of apoptosis in liver, heart, and nerve tissue and a regulator of inflammation in the skin and colon (10)(11)(12)(13)32). This study showed that the expression of ASK1 was elevated in human GC tissue.…”

Section: Discussionmentioning

confidence: 56%

“…Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.…”

Section: Jnk | C-junmentioning

confidence: 99%

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Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Mitogen-activated protein kinase (MAPK) pathways regulate multiple cellular functions and are highly active in many types of human cancers. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream MAPK involved in apoptosis, inflammation, and carcinogenesis. This study investigated the role of ASK1 in the development of gastric cancer. In human gastric cancer specimens, we observed increased ASK1 expression, compared to nontumor epithelium. Using a chemically induced murine gastric tumorigenesis model, we observed increased tumor ASK1 expression, and ASK1 knockout mice had both fewer and smaller tumors than wild-type (WT) mice. ASK1 siRNA inhibited cell proliferation through the accumulation of cells in G1 phase of the cell cycle, and reduced cyclin D1 expression in gastric cancer cells, whereas these effects were uncommon in other cancer cells. ASK1 overexpression induced the transcription of cyclin D1, through AP-1 activation, and ASK1 levels were regulated by cyclin D1, via the Rb-E2F pathway. Exogenous ASK1 induced cyclin D1 expression, followed by elevated expression of endogenous ASK1. These results indicate an autoregulatory mechanism of ASK1 in the development of gastric cancer. Targeting this positive feedback loop, ASK1 may present a potential therapeutic target for the treatment of advanced gastric cancer. JNK | c-JunG astric cancer (GC) is a common cancer worldwide, associated with a high mortality despite its declining incidence in recent decades. Smoking, salted or smoked foods, and Helicobacter pylori appear to be major environmental inducers of GC (1-3). Although the role of H. pylori in causing mucosal effects has been investigated, which molecular signal(s) initiate the program of irreversible transformation remain unclear, and thus molecular targeting therapies for GC have not been well established.Mitogen-activated protein kinase (MAPK) pathways are important for the development of gastric tumorigenesis (4). Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed MAPK kinase kinase (MAP3K), activated by various stress stimuli, including reactive oxygen species (ROS), TNF-α, and LPS (5-7). ASK1 activates the JNK and p38 signaling pathways and is required for both oxidative stress and cytokine-induced apoptosis (5). Furthermore, ASK1 affects multiple cellular functions, including survival, differentiation, and the innate immune response (5,7,8) and has been reported to be involved in the pathogenesis of various human diseases, including neurodegenerative (9), cardiovascular (10), and inflammatory diseases (11,12). Additionally, ASK1 has been shown to participate in both colon (12) and skin (13) tumorigenesis through the regulation of inflammation and apoptosis. However, no reported study has demonstrated a role for ASK1 in gastric tumorigenesis.In this study, we examined the role of ASK1 in gastric tumorigenesis using both human GC samples and ASK1-deficient (ASK1 −/− ) mice. We demonstrated that ASK1 is important for gastric tumorigenesis through the regulation of cyclin D1 e...

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Section: Discussionmentioning

confidence: 56%

Section: Jnk | C-junmentioning

confidence: 99%

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Hayakawa

Hirata

Nakagawa

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Different from the expression pattern of ASK1 or ASK2 (ref. 24), ASK3 was predominantly detected in the kidney by realtime quantitative PCR analysis ( Fig. 1c) and immunoblot analysis probed with an ASK3-specific antibody ( Fig.…”

Section: Resultsmentioning

confidence: 99%

ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney

et al. 2012

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Changes in the osmolality of body fluids pose a serious danger to cells and living organisms, which have developed cellular systems to sense and respond to osmotic stress and to maintain homoeostasis of body fluid. However, these processes are incompletely understood in mammals. Here we show that apoptosis signal-regulating kinase 3 (ASK3) is predominantly expressed in the kidney and alters its kinase activity bidirectionally in response to osmotic stress. We further demonstrate that ASK3 interacts with WNK1, mutation in which causes an inherited form of hypertension in humans. Knockdown of Ask3 by short interfering RNA enhances the activation of the WNK1-SPAK/OSR1 signalling pathway. Moreover, Ask3 knockout mice exhibit a hypertensive phenotype, in addition to hyperactivation of SPAK/OSR1 in renal tubules. Our results suggest that ASK3 is a unique bidirectional responder to osmotic stress and that it has a role in the control of blood pressure as an upstream suppressor of the WNK1-SPAK/OSR1 signalling pathway.

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“…15 There was only one methylated (>33%) locus shared between any of the mouse medulloblastoma tumors and the patient sample. Common to SmoA2 and the patient sample was FAM83F (family with sequence similarity 83, member F), a gene of unknown function.…”

Section: Mouse Models Of Medulloblastoma Lack Extensive Promoter Cpg mentioning

confidence: 99%

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

et al. 2013

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

Cited by 120 publications

References 39 publications

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

Apoptosis signal-regulating kinase 1 and cyclin D1 compose a positive feedback loop contributing to tumor growth in gastric cancer

ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney

Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer

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