title: Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4.
abstract: The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination. Sek1(-/- )embryos display severe anemia and die between embryonic day 10.5 (E10.5) and E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are normal in sek1(-/- )embryos. However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/- )embryos had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(-/-) liver cells underwent massive apoptosis. These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes.
authors.affiliation: The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Suite 706, Toronto, Ontario M5G 2C1, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Nishina
authors.forename: C
authors.initials: C
authors.lastname: Vaz
authors.forename: P
authors.initials: P
authors.lastname: Billia
authors.forename: M
authors.initials: M
authors.lastname: Nghiem
authors.forename: T
authors.initials: T
authors.lastname: Sasaki
authors.forename: J L
authors.initials: JL
authors.lastname: De la Pompa
authors.forename: K
authors.initials: K
authors.lastname: Furlonger
authors.forename: C
authors.initials: C
authors.lastname: Paige
authors.forename: C
authors.initials: C
authors.lastname: Hui
authors.forename: K D
authors.initials: KD
authors.lastname: Fischer
authors.forename: H
authors.initials: H
authors.lastname: Kishimoto
authors.forename: T
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: T
authors.initials: T
authors.lastname: Katada
authors.forename: J R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D018390:Gene Targeting; D006410:Hematopoiesis / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000196:embryology*; D048670:MAP Kinase Kinase 4; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D016296:Mutagenesis; D018919:Neovascularization, Physiologic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*
chemical_list: D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases