title: Apoptosis signal-regulating kinase 1 inhibits hepatocarcinogenesis by controlling the tumor-suppressing function of stress-activated mitogen-activated protein kinase.
abstract: The stress-activated mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal kinase (JNK), and p38 have been implicated in hepatocarcinogenesis. Although the many interrelated functions of JNK and p38 are precisely regulated by upstream signaling molecules, little is known about upstream regulators. We investigated the role of apoptosis signal-regulating kinase 1 (ASK1), a major player in the regulation of JNK and p38 activities, in hepatocarcinogenesis using a mouse hepatocellular carcinoma (HCC) model. ASK1-deficient (ASK1(-/-) ) and wildtype (WT) mice were treated with diethylnitrosamine on postnatal day 14. Strikingly, after 7 months, approximately three times as many tumors developed in ASK1(-/-) mice as in WT mice. Although JNK and p38 activation were attenuated in ASK1(-/-) HCCs relative to WT HCCs, cell proliferation was comparable in HCCs from both types of mice. On the other hand, both cancer cell apoptosis and hyperphosphorylation of BimEL, a proapoptotic Bcl-2 family member, were suppressed in the ASK1(-/-) HCCs. ASK1(-/-) mice showed remarkable resistance to Fas-induced hepatocyte apoptosis in vivo, probably because of attenuated JNK-mediated BimEL phosphorylation and mitochondrial apoptotic pathway activation. The reintroduction of ASK1 to ASK1(-/-) mouse liver using an adenoviral vector restored Fas-induced hepatocyte death and phosphorylation of JNK and BimEL. Similar findings were obtained in tumor necrosis factor alpha-induced hepatocyte apoptosis. Furthermore, ASK1 was involved in DNA damage-induced p21 up-regulation through a p38 pathway.
  
  
  CONCLUSIONS
  ASK1 is involved in death receptor-mediated apoptosis and DNA-damage response by way of stress-activated MAPK in the liver, and thus acts as a tumor suppressor in hepatocarcinogenesis. This study provides new insight into the regulation of stress- activated MAPK signaling in hepatocarcinogenesis.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Takeda
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Takehiro
authors.initials: T
authors.lastname: Sato
authors.forename: Hiroto
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Wachiko
authors.initials: W
authors.lastname: Nakata
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D049109:Cell Proliferation; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D048670:MAP Kinase Kinase 4 / Q000502:physiology; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D004052:Diethylnitrosamine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D048670:MAP Kinase Kinase 4