YC-1-inhibited proliferation of rat mesangial cells through suppression of cyclin D1-independent of cGMP pathway and partially reversed by p38 MAPK inhibitor.
This study was designed to investigate the effect of 1-benzyl-3-(5'-hydroxymethyl-2'-furyl) indazole (YC-1), a guanylate cyclase activator, upon the proliferation of rat mesangial cells and its underlying mechanism. YC-1 inhibited cell proliferation and DNA synthesis in a dose- and time-dependent manner. Flow cytometry cell-cycle studies revealed that YC-1 prevented the entry of cells from G1 into S phase. The expression of cyclin D1 and the kinase activity of cyclin D1/cyclin-dependent kinase (CDK)4 were lower within YC-1-treated cells, revealed by Western blotting, Northern blotting and kinase assays. YC-1 did not increase the intracellular cGMP concentration in mesangial cells. Inhibitors of soluble guanylate cyclase, protein kinase G, or protein kinase A also did not reverse the inhibitory effect elicited by YC-1, while co-treatment with p38 mitogen-activated protein kinase (MAPK) inhibitor could partially reverse the suppressive effect. YC-1 inhibited proliferation of mesangial cells and induced cell-cycle arrest by the reduction of cyclin D1 synthesis and cyclin D1/CDK4 kinase activity. This effect acts partially through p38 MAPK signal transduction activation and is independent of cGMP-signaling pathways.
Chiang
Wen-Chih
WC
Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10016, Taiwan.
Teng
Che-Ming
CM
Lin
Shuei-Liong
SL
Chen
Yung-Ming
YM
Tsai
Tun-Jun
TJ
Hsieh
Bor-Shen
BS
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D012995:Solubility; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D001973:Bromodeoxyuridine; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D006152:Cyclic GMP; D019938:Cyclin D1; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006162:Guanylate Cyclase; D007093:Imidazoles; D007191:Indazoles; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C493958:Cdkn1a protein, rat; C493962:Cdkn1b protein, rat; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; C093642:SB 203580