Substance P-induced activation of p42/44 mitogen-activated protein kinase associated with cell proliferation in human tracheal smooth muscle cells.
Substance P (SP) released from sensory nerve endings in the airways induces several responses including cell proliferation. However, the mechanisms were not completely understood in tracheal smooth muscle cells (TSMCs). We therefore investigated the effect of SP on cell proliferation and activation of p42/p44 mitogen-activated protein kinase (MAPK) in these cells. SP stimulated [3H]thymidine incorporation and p42/p44 MAPK phosphorylation in a time- and concentration-dependent manner in TSMCs. Both DNA synthesis and phosphorylation of MAPK in response to SP were attenuated by pretreatment with pertussis toxin, genistein, D609, U73122, staurosporine, removal of Ca(2+) by BAPTA/AM plus EGTA, PD98059, and SB202190. Furthermore, overexpression of dominant negative mutants, H-Ras-15A and Raf-N4, significantly suppressed p42/p44 MAPK activation induced by SP and PDGF-BB. These results conclude that the mitogenic effect of SP was mediated through the activation of Ras/Raf/MEK/MAPK pathway, which was modulated by PC-PLC, PI-PLC, Ca(2+), and PKC in cultured human TSMCs.
Yang
Chuen-Mao
CM
Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, 259 Wen-Hwa 1 Road, Kwei-San, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw
Hsiao
Li-Der
LD
Chien
Chin-Sung
CS
Lin
Chih-Chung
CC
Luo
Shu-Fen
SF
Wang
Chuan-Chwan
CC
D001249:Asthma / Q000378:metabolism / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000378:metabolism / Q000503:physiopathology; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology; D013936:Thymidine; D014132:Trachea / Q000166:cytology / Q000294:innervation / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D020033:Protein Isoforms; D013373:Substance P; D004247:DNA; D019833:Genistein; D037342:Pertussis Toxin; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D010738:Type C Phospholipases; D013936:Thymidine