PMID- 11306243
OWN - NLM
STAT- MEDLINE
DCOM- 20010719
LR  - 20190921
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 13
IP  - 4
DP  - 2001 Apr
TI  - Mechanisms of thrombin-induced MAPK activation associated with cell proliferation 
      in human cultured tracheal smooth muscle cells.
PG  - 257-67
AB  - The elevated level of thrombin has been detected in the airway fluids of 
      asthmatic patients. However, the implication of thrombin in the pathogenesis of 
      bronchial hyperreactivity was not completely understood. Therefore, in this study 
      we investigated the effect of thrombin on cell proliferation and p42/p44 
      mitogen-activated protein kinase (MAPK) activation in human tracheal smooth 
      muscle cells (TSMCs). Thrombin stimulated [3H]thymidine incorporation and p42/p44 
      MAPK phosphorylation in a time- and concentration-dependent manner in TSMCs. 
      Pretreatment of TSMCs with pertussis toxin (PTX) significantly inhibited 
      [3H]thymidine incorporation and phosphorylation of MAPK induced by thrombin. 
      These responses were attenuated by tyrosine kinase inhibitors genistein and 
      herbimycin A, phosphatidyl inositide (PI)-phospholipase C (PLC) inhibitor U73122, 
      protein kinase C (PKC) inhibitor GF109203X, removal of Ca(2+) by addition of 
      BAPTA/AM plus EGTA, and PI 3-kinase inhibitors wortmannin and LY294002. In 
      addition, thrombin-induced [3H]-thymidine incorporation and p42/p44 MAPK 
      phosphorylation was completely inhibited by PD98059 (an inhibitor of MEK1/2), 
      indicating that activation of MEK1/2 was required for these responses. 
      Furthermore, overexpression of dominant negative mutants, RasN17 and Raf-301, 
      significantly suppressed p42/p44 MAPK activation induced by thrombin and PDGF-BB, 
      indicating that Ras and Raf may be required for activation of these kinases. 
      These results conclude that the mitogenic effect of thrombin was mediated through 
      the activation of Ras/Raf/MEK/MAPK pathway. Thrombin-mediated MAPK activation was 
      modulated by PI-PLC, Ca(2+), PKC, tyrosine kinase, and PI 3-kinase associated 
      with cell proliferation in cultured human TSMCs.
FAU - Lin, C C
AU  - Lin CC
AD  - Department of Physiology and Pharmacology, College of Medicine, Chang Gung 
      University, Kwei-San, Tao-Yuan, Taiwan.
FAU - Shyr, M H
AU  - Shyr MH
FAU - Chien, C S
AU  - Chien CS
FAU - Wang, C C
AU  - Wang CC
FAU - Chiu, C T
AU  - Chiu CT
FAU - Hsiao, L D
AU  - Hsiao LD
FAU - Yang, C M
AU  - Yang CM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cell Signal
JT  - Cellular signalling
JID - 8904683
RN  - 0 (Androstadienes)
RN  - 0 (Benzoquinones)
RN  - 0 (Chelating Agents)
RN  - 0 (Chromones)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Estrenes)
RN  - 0 (Flavonoids)
RN  - 0 (Indoles)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Maleimides)
RN  - 0 (Morpholines)
RN  - 0 (Protein Isoforms)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Quinones)
RN  - 0 (Virulence Factors, Bordetella)
RN  - 112648-68-7 
      (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione)
RN  - 1W306TDA6S (Rifabutin)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - 526U7A2651 (Egtazic Acid)
RN  - 70563-58-5 (herbimycin)
RN  - DH2M523P0H (Genistein)
RN  - EC 2.4.2.31 (Pertussis Toxin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - K22DDW77C0 (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)
RN  - L79H6N0V6C (bisindolylmaleimide I)
RN  - SJE1IO5E3I (2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one)
RN  - XVA4O219QW (Wortmannin)
SB  - IM
MH  - Androstadienes/pharmacology
MH  - Benzoquinones
MH  - Blotting, Western
MH  - Cell Division
MH  - Cells, Cultured
MH  - Chelating Agents/pharmacology
MH  - Chromones/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Egtazic Acid/analogs & derivatives/pharmacology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Estrenes/pharmacology
MH  - Flavonoids/pharmacology
MH  - Genistein/pharmacology
MH  - Humans
MH  - Indoles/pharmacology
MH  - Lactams, Macrocyclic
MH  - *MAP Kinase Signaling System
MH  - Maleimides/pharmacology
MH  - Mitogen-Activated Protein Kinase 1/chemistry/metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinases/chemistry/metabolism
MH  - Morpholines/pharmacology
MH  - Muscle, Smooth/*cytology/*enzymology
MH  - Pertussis Toxin
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Protein Isoforms
MH  - Protein Kinase C/metabolism
MH  - Proto-Oncogene Proteins c-raf/metabolism
MH  - Pyrrolidinones/pharmacology
MH  - Quinones/pharmacology
MH  - Rifabutin/analogs & derivatives
MH  - Thrombin/metabolism/pharmacology
MH  - Time Factors
MH  - Trachea/*cytology
MH  - Transfection
MH  - Virulence Factors, Bordetella/pharmacology
MH  - Wortmannin
MH  - ras Proteins/metabolism
EDAT- 2001/04/18 10:00
MHDA- 2001/07/20 10:01
CRDT- 2001/04/18 10:00
PHST- 2001/04/18 10:00 [pubmed]
PHST- 2001/07/20 10:01 [medline]
PHST- 2001/04/18 10:00 [entrez]
AID - S0898-6568(01)00134-6 [pii]
AID - 10.1016/s0898-6568(01)00134-6 [doi]
PST - ppublish
SO  - Cell Signal. 2001 Apr;13(4):257-67. doi: 10.1016/s0898-6568(01)00134-6.