PMID- 11812655
OWN - NLM
STAT- MEDLINE
DCOM- 20020520
LR  - 20220321
IS  - 0898-6568 (Print)
IS  - 0898-6568 (Linking)
VI  - 14
IP  - 3
DP  - 2002 Mar
TI  - Thrombin-stimulated cell proliferation mediated through activation of 
      Ras/Raf/MEK/MAPK pathway in canine cultured tracheal smooth muscle cells.
PG  - 265-75
AB  - The elevated level of thrombin has been detected in the airway fluids of 
      asthmatic patients and shown to stimulate cell proliferation in tracheal smooth 
      muscle cells (TSMCs). However, the implication of thrombin in the cell 
      proliferation was not completely understood. In this study, thrombin stimulated 
      [3H]thymidine incorporation and p42/p44 mitogen-activated protein kinase (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 inhibitor GF109203X, removal of Ca2+ by addition of BAPTA/AM 
      plus EGTA, PI 3-kinase inhibitors wortmannin and LY294002, and inhibitor of 
      MEK1/2 PD98059. Furthermore, overexpression of dominant negative mutants, 
      H-Ras-15A and Raf-N4, 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, Ca2+, PKC, tyrosine 
      kinase, and PI 3-kinase associated with cell proliferation in canine cultured 
      TSMCs.
FAU - Lin, Chih-Chung
AU  - Lin CC
AD  - Department of Physiology and Pharmacology, College of Medicine, Chang Gung 
      University, 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan, Taiwan, ROC.
FAU - Shyr, Ming-Hwang
AU  - Shyr MH
FAU - Chien, Chin-Sung
AU  - Chien CS
FAU - Wang, Chuan-Chwan
AU  - Wang CC
FAU - Chiu, Chi-Tso
AU  - Chiu CT
FAU - Hsiao, Li-Der
AU  - Hsiao LD
FAU - Yang, Chuen-Mao
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 (Enzyme Inhibitors)
RN  - 0 (Estrenes)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Pyrrolidinones)
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  - 9007-49-2 (DNA)
RN  - EC 2.4.2.31 (Pertussis Toxin)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine 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 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 2)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
RN  - EC 3.1.4.11 (Phosphoinositide Phospholipase C)
RN  - EC 3.4.21.5 (Thrombin)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 4.6.1.13 (Phosphatidylinositol Diacylglycerol-Lyase)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/metabolism
MH  - Cell Division/drug effects
MH  - Cells, Cultured
MH  - DNA/biosynthesis
MH  - Dogs
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Estrenes/pharmacology
MH  - Female
MH  - MAP Kinase Kinase 1
MH  - MAP Kinase Kinase 2
MH  - MAP Kinase Signaling System/*physiology
MH  - Male
MH  - Mitogen-Activated Protein Kinase 1/*metabolism
MH  - Mitogen-Activated Protein Kinase 3
MH  - Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
MH  - Mitogen-Activated Protein Kinases/*metabolism
MH  - Muscle, Smooth, Vascular/cytology
MH  - Pertussis Toxin
MH  - Phosphatidylinositol Diacylglycerol-Lyase
MH  - Phosphoinositide Phospholipase C
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation
MH  - Protein Kinase C/antagonists & inhibitors
MH  - Protein Serine-Threonine Kinases/antagonists & inhibitors
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Proto-Oncogene Proteins c-raf/genetics/*metabolism
MH  - Proto-Oncogene Proteins p21(ras)/genetics/*metabolism
MH  - Pyrrolidinones/pharmacology
MH  - Thrombin/*metabolism/pharmacology
MH  - Trachea/cytology
MH  - Type C Phospholipases/antagonists & inhibitors
MH  - Virulence Factors, Bordetella/pharmacology
EDAT- 2002/01/29 10:00
MHDA- 2002/05/22 10:01
CRDT- 2002/01/29 10:00
PHST- 2002/01/29 10:00 [pubmed]
PHST- 2002/05/22 10:01 [medline]
PHST- 2002/01/29 10:00 [entrez]
AID - S0898656801002492 [pii]
AID - 10.1016/s0898-6568(01)00249-2 [doi]
PST - ppublish
SO  - Cell Signal. 2002 Mar;14(3):265-75. doi: 10.1016/s0898-6568(01)00249-2.