| Chang MS |
------>authors3_c= ------>paper_class1=1 ------>Impact_Factor=4.612 ------>paper_class3=2 ------>paper_class2=1 ------>vol=66 ------>confirm_bywho=chlin ------>insert_bywho=chlin ------>Jurnal_Rank=11.4 ------>authors4_c= ------>comm_author=1 ------>patent_EDate=None ------>authors5_c= ------>publish_day=1 ------>paper_class2Letter=None ------>page2=571 ------>medlineContent= ------>unit=E0200 ------>insert_date=20041025 ------>iam=5 ------>update_date=None ------>author=??? ------>change_event=4 ------>ISSN= ------>authors_c= ------>score=342 ------>journal_name=Mol. Pharmacol. ------>paper_name=YC-1-induced cyclooxygenase-2 expression is mediated by cGMP-dependent activations of Ras, Akt, and NF-kB in human pulmonary epithelial cell ------>confirm_date=20070505 ------>tch_id=085007 ------>pmid=15322248 ------>page1=561 ------>fullAbstract=We demonstrated previously that 3-(5~-hydroxymethyl-2~-furyl)-1-benzylindazole (YC-1), an activator of soluble guanylate cyclase (sGC), induces cyclooxygenase-2 (COX-2) expression via cGMP- and p44/42 mitogen-activated protein kinase-dependent pathways in human pulmonary epithelial A549 cells. In this study, we explore the role of Ras, phosphoinositide-3-OH-kinase (PI3K), Akt, and transcription factor nuclear factor-kappaB (NF-kappaB) in YC-1-induced COX-2 expression in A549 cells. A Ras inhibitor (manumycin A), a PI3K inhibitor (wortmannin), an Akt inhibitor (1l-6-Hydroxymethyl-chiro-inositol2-[(R)-2-O-methyl-3-O-octadecylcarbonate ]), and an NF-kappaB inhibitor [pyrrolidine dithiocarbamate (PDTC)] all reduced YC-1-induced COX-2 expression. The YC-1-induced increase in COX activity was also blocked by manumycin A, wortmannin, PDTC, and the dominant-negative mutants for Ras (RasN17), Akt (Akt DN), and IkappaBalpha (IkappaBalphaM). The YC-1-induced increase in Ras activity was inhibited by an sGC inhibitor [1H-(1,2,4)oxadiazolo[4,3-a]quinozalin-1-one (ODQ)], a protein kinase G (PKG) inhibitor [1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3~,2~,1~-kl]pyrrolo[3,4-I][1,6]benz odiazocine-10-carboxylic acid methyl ester (KT-5823)], and manumycin A. YC-1-induced Akt activation was also inhibited by ODQ, KT-5823, manumycin A, and wortmannin. YC-1 caused the formation of an NF-kappaB-specific DNA-protein complex and an increase in kappaB-luciferase activity. YC-1-induced kappaB-luciferase activity was inhibited by ODQ, KT-5823, manumycin A, wortmannin, an Akt inhibitor, PDTC, RasN17, Akt DN, and IkappaBalphaM. Likewise, YC-1-induced IKKalpha/beta activation was inhibited by ODQ, KT-5823, manumycin A, wortmannin, and an Akt inhibitor. Furthermore, YC-1-induced COX-2 promoter activity was inhibited by manumycin A, RasN17, Akt DN, PDTC, and IkappaBalphaM. Taken together, these results indicate that YC-1 might activate the sGC/cGMP/PKG pathway to induce Ras and PI3K/Akt activation, which in turn initiates IKKalpha/beta and NF-kappaB activation and finally induces COX-2 expression in A549 cells. ------>tmu_sno=None ------>sno=10045 ------>authors2=Lee WS ------>authors3=Chen BC ------>authors4=Sheu JR ------>authors5=Lin CH ------>authors6= ------>authors6_c= ------>authors=Chang MS ------>delete_flag=0 ------>SCI_JNo=None ------>authors2_c= ------>publish_area=0 ------>updateTitle=YC-1-induced cyclooxygenase-2 expression is mediated by cGMP-dependent activations of Ras, phosphoinositide-3-OH-kinase, Akt, and nuclear factor-kappaB in human pulmonary epithelial cells. ------>language=2 ------>check_flag=None ------>submit_date=None ------>country=None ------>no= ------>patent_SDate=None ------>update_bywho=None ------>publish_year=2004 ------>submit_flag=None ------>publish_month=1 |