title: Plasmin decreases the BH3-only protein BimEL via the ERK1/2 signaling pathway in hepatocytes.
abstract: Since the signal transduction mechanisms responsible for liver regeneration mediated by the plasminogen/plasmin system remain largely undetermined, we have investigated whether plasmin regulates the pro-apoptotic protein Bim(EL) in primary hepatocytes. Plasmin bound to hepatocytes in part via its lysine binding sites (LBS). Plasmin also triggered phosphorylation of ERK1/2 without cell detachment. The plasmin-induced phosphorylation of ERK1/2 was inhibited by the LBS inhibitor epsilon-aminocaproic acid (EACA), the serine protease inhibitor aprotinin, and the MEK inhibitor PD98059. DFP-inactivated plasmin failed to phosphorylate ERK1/2. Plasmin temporally decreased the starvation-induced expression of Bim(EL) and activation of caspase-3 via the ERK1/2 signaling pathway, resulting in an enhancement of cell survival. The amount of mRNA for Bim increased 1 day after the injection of CCl(4) in livers of plasminogen knockout (Plg-KO) and the wild-type (WT) mice. The increase in Bim(EL) protein persisted for at least 7 days post-injection in livers of Plg-KO mice, whereas WT mice showed an increase in Bim(EL) protein 1 day after the injection. Plg-KO and WT mice showed notable phosphorylation of ERK1/2 7 and 3 days after the injection of CCl(4), respectively. Our data suggest that the plasminogen/plasmin system could decrease Bim(EL) expression via the ERK1/2 signaling pathway during liver regeneration.
authors.affiliation: Department of Physiology, School of Medicine, Kinki University, 377-2, Ohnohigashi, Osakasayama, 589-8511, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.forename: Syuhei
authors.initials: S
authors.lastname: Kawata
authors.forename: Chikako
authors.initials: C
authors.lastname: Okamoto
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Tsuritani
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ueshima
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsuo
mesh_terms: D015119:Aminocaproic Acid / Q000494:pharmacology; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D007611:Aprotinin / Q000494:pharmacology; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007531:Isoflurophate / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000933:Antifibrinolytic Agents; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D005343:Fibrinolytic Agents; D005419:Flavonoids; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D007531:Isoflurophate; D010958:Plasminogen; D007611:Aprotinin; D002251:Carbon Tetrachloride; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D005341:Fibrinolysin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D015119:Aminocaproic Acid