title: Substance P-induced activation of p42/44 mitogen-activated protein kinase associated with cell proliferation in human tracheal smooth muscle cells.
abstract: 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.
authors.affiliation: 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
authors.forename: Chuen-Mao
authors.initials: CM
authors.lastname: Yang
authors.forename: Li-Der
authors.initials: LD
authors.lastname: Hsiao
authors.forename: Chin-Sung
authors.initials: CS
authors.lastname: Chien
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Luo
authors.forename: Chuan-Chwan
authors.initials: CC
authors.lastname: Wang
mesh_terms: 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
chemical_list: 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