Role of isoprenylcysteine carboxyl methyltransferase in tumor necrosis factor-alpha stimulation of expression of vascular cell adhesion molecule-1 in endothelial cells.
We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-L-cysteine (AFC) or N-acetyl-S-geranylgeranyl-L-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-alpha (TNF-alpha) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-alpha stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-alpha. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-alpha stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.
Ahmad
Mushtaq
M
Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Ga 30322, USA. mahmad@emory.edu
Zhang
Yan
Y
Zhang
Yong
Y
Papharalambus
Christopher
C
Alexander
R Wayne
RW
D000111:Acetylcysteine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000952:Antigens, Polyomavirus Transforming; D001011:Aorta / Q000166:cytology / Q000821:virology; D002461:Cell Line, Transformed / Q000821:virology; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004224:Diterpenes / Q000009:adverse effects / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008745:Methylation; D011496:Protein Methyltransferases / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D004224:Diterpenes; D004791:Enzyme Inhibitors; C095716:N-acetyl-S-geranylgeranyl-cysteine; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006861:Hydrogen Peroxide; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D020830:rac1 GTP-Binding Protein; D003545:Cysteine; C068268:N-acetyl-S-farnesylcysteine; D000111:Acetylcysteine