title: SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis.
abstract: Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5. Although a defect in liver formation is accompanied with the embryonic lethality of sek1(-/-) mice, the mechanism of the liver defect has remained unknown. In the present study, we first produced a monoclonal antibody specifically recognizing murine hepatoblasts for the analysis of liver development and further investigated genetic interaction ofsek1 with tumor necrosis factor-alpha receptor 1 gene (tnfr1) and protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek1(-/-) embryos was not protected by additionaltnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-kappaB signaling components. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to E12.5. Instead, impaired hepatoblast proliferation was observed in sek1(-/-) livers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek1(-/-) livers was more severe than in c-jun(-/-) embryos, and sek1(-/-) c-jun(-/-) embryos died more rapidly before E8.5. The hepatoblast proliferation required no hematopoiesis, since liver development was not impaired in AML1(-/-) mice that lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek1(-/-) livers. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from NF-kappaB or c-Jun.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, 113-0033, Japan
authors.forename: Tomomi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohata
authors.forename: Daiju
authors.initials: D
authors.lastname: Kitagawa
authors.forename: Gen
authors.initials: G
authors.lastname: Nishitai
authors.forename: Jungwon
authors.initials: J
authors.lastname: Seo
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tanemura
authors.forename: Nao
authors.initials: N
authors.lastname: Shimizu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Teiji
authors.initials: T
authors.lastname: Wada
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Miyuki
authors.initials: M
authors.lastname: Mochita
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers; D002452:Cell Count; D002455:Cell Division; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006410:Hematopoiesis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015415:Biomarkers; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D017228:Hepatocyte Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases