title: G(alpha)12/13 induction of CYR61 in association with arteriosclerotic intimal hyperplasia: effect of sphingosine-1-phosphate.
abstract: OBJECTIVE
  Gα(12/13) play a role in oncogenic transformation and tumor growth. Cysteine-rich protein 61 (CYR61) is a growth-factor-inducible angiogenic factor. In view of potential overlapping functions between Gα(12/13) and CYR61, this study investigated the role of these G proteins in CYR61 induction in association with hyperplastic vascular abnormality.
  
  
  RESULTS
  Overexpression of activated Gα(12) or Gα(13) induced CYR61 expression in vascular smooth muscle cells (VSMCs). Gene knockdown and knockout experiments revealed that sphingosine-1-phosphate (S1P) treatment induced CYR61 via Gα(12/13). JunD/activator protein-1 (AP-1) was identified as a transcription factor required for CYR61 transactivation by S1P. Deficiencies in Gα(12/13) abrogated AP-1 activation and AP-1-mediated CYR61 induction. c-Jun N-terminal kinase was responsible for CYR61 induction. Moreover, deficiencies of Gα(12/13) abolished c-Jun N-terminal kinase-dependent CYR61 induction by S1P. N-acetyl-l-cysteine or NADPH oxidase inhibitor treatment reversed CYR61 induction by S1P, indicating that reactive oxygen species are responsible for this process. The levels of Gα(12/13) were increased within thickened intimas and medias in wire-injured mouse femoral arteries, which was accompanied by simultaneous CYR61 induction. Moreover, Gα(12/13) and CYR61 were costained in the arteriosclerotic lesions immediately adjacent to human tumor tissues.
  
  
  CONCLUSIONS
  Gα(12/13) regulate AP-1-dependent CYR61 induction in VSMCs and promote VSMC migration, and they are upregulated with CYR61 in arteriosclerotic lesions.
authors.affiliation: Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of PharmaceuticalSciences, Seoul, South Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
authors.forename: Chang Yeob
authors.initials: CY
authors.lastname: Han
authors.forename: Hee Yeon
authors.initials: HY
authors.lastname: Kay
authors.forename: Il Je
authors.initials: IJ
authors.lastname: Cho
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Ki
authors.forename: Moo Yeol
authors.initials: MY
authors.lastname: Lee
authors.forename: Hyuck Moon
authors.initials: HM
authors.lastname: Kwon
authors.forename: Chang Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D000368:Aged; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006965:Hyperplasia; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D019255:NADPH Oxidases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; C501849:CCN1 protein, rat; D055515:Cysteine-Rich Protein 61; D008246:Lysophospholipids; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; C060506:sphingosine 1-phosphate; D019255:NADPH Oxidases; D048031:JNK Mitogen-Activated Protein Kinases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D013110:Sphingosine