Phosphoinositide 3-kinase-dependent Ras activation by tauroursodesoxycholate in rat liver

被引:49
作者
Kurz, AK
Block, C
Graf, D
vom Dahl, S
Schliess, F
Häussinger, D
机构
[1] Univ Dusseldorf, Med Einrichtungen, Klin Gastroenterol Heparol & Infektiol, D-40225 Dusseldorf, Germany
[2] Max Planck Inst Mol Physiol, D-44202 Dortmund, Germany
关键词
bile salt; cholestasis; hepatocytes; MAP kinases; signal transduction;
D O I
10.1042/0264-6021:3500207
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Ursodesoxycholic acid, widely used for the treatment of cholestatic liver disease, causes choleretic, anti-apoptotic and immunomodulatory effects. Here the effects on choleresis of its taurine conjugate tauroursodesoxycholate (TUDC), which is present in the enterohepatic circulation, were correlated with the activation of important elements of intracellular signal transduction in cultured rat hepatocytes and perfused rat liver. TUDC induced a time- and concentration-dependent activation of the small GTP-binding protein Pas and of phosphoinositide 3-kinase PI 3-kinase) in cultured hepatocytes. Ras activation was dependent on PI3-kinase activity, without the involvement of protein kinase C- and genistein-sensitive tyrosine kinases. Ras activation by TUDC was followed by an activation of the mitogen-activated protein kinases extracellular-signal-regulated kinase-1 (Erk-1) and Erk-2. In perfused rat liver, PI 3-kinase inhibitors largely abolished the stimulatory effect of TUDC on taurocholate excretion, suggesting an important role for a PI 3-kinase/Ras/Erk pathway in the choleretic effect of TUDC.
引用
收藏
页码:207 / 213
页数:7
相关论文
共 56 条
  • [1] PD-098059 IS A SPECIFIC INHIBITOR OF THE ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE IN-VITRO AND IN-VIVO
    ALESSI, DR
    CUENDA, A
    COHEN, P
    DUDLEY, DT
    SALTIEL, AR
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (46) : 27489 - 27494
  • [2] Benz C, 1998, EUR J CLIN INVEST, V28, P577
  • [3] Tauroursodeoxycholic acid activates protein kinase C in isolated rat hepatocytes
    Beuers, U
    Throckmorton, DC
    Anderson, MS
    Isales, CM
    Thasler, W
    KullakUblick, GA
    Sauter, G
    Koebe, HG
    Paumgartner, G
    Boyer, JL
    [J]. GASTROENTEROLOGY, 1996, 110 (05) : 1553 - 1563
  • [4] EFFECTS OF TAUROURSODEOXYCHOLIC ACID ON CYTOSOLIC CA2+ SIGNALS IN ISOLATED RAT HEPATOCYTES
    BEUERS, U
    NATHANSON, MH
    BOYER, JL
    [J]. GASTROENTEROLOGY, 1993, 104 (02) : 604 - 612
  • [5] URSODEOXYCHOLIC ACID FOR TREATMENT OF PRIMARY SCLEROSING CHOLANGITIS - A PLACEBO-CONTROLLED TRIAL
    BEUERS, U
    SPENGLER, U
    KRUIS, W
    AYDEMIR, U
    WIEBECKE, B
    HELDWEIN, W
    WEINZIERL, M
    PAPE, GR
    SAUERBRUCH, T
    PAUMGARTNER, G
    [J]. HEPATOLOGY, 1992, 16 (03) : 707 - 714
  • [6] TAUROURSODEOXYCHOLIC ACID STIMULATES HEPATOCELLULAR EXOCYTOSIS AND MOBILIZES EXTRACELLULAR CA++ MECHANISMS DEFECTIVE IN CHOLESTASIS
    BEUERS, U
    NATHANSON, MH
    ISALES, CM
    BOYER, JL
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 1993, 92 (06) : 2984 - 2993
  • [7] Quantitative structure-activity analysis correlating Ras/Raf interaction in vitro to Raf activation in vivo
    Block, C
    Janknecht, R
    Herrmann, C
    Nassar, N
    Wittinghofer, A
    [J]. NATURE STRUCTURAL BIOLOGY, 1996, 3 (03): : 244 - 251
  • [8] PROTEINS REGULATING RAS AND ITS RELATIVES
    BOGUSKI, MS
    MCCORMICK, F
    [J]. NATURE, 1993, 366 (6456) : 643 - 654
  • [9] CAMP ANTAGONIZES P21(RAS)-DIRECTED ACTIVATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE-2 AND PHOSPHORYLATION OF MSOS NUCLEOTIDE EXCHANGE FACTOR
    BURGERING, BMT
    PRONK, GJ
    VANWEEREN, PC
    CHARDIN, P
    BOS, JL
    [J]. EMBO JOURNAL, 1993, 12 (11) : 4211 - 4220
  • [10] INVOLVEMENT OF MICROTUBULES IN THE LINK BETWEEN CELL-VOLUME AND PH OF ACIDIC CELLULAR COMPARTMENTS IN RAT AND HUMAN HEPATOCYTES
    BUSCH, GL
    SCHREIBER, R
    DARTSCH, PC
    VOLKL, H
    DAHL, SV
    HAUSSINGER, D
    LANG, F
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (19) : 9165 - 9169