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Vol. 14, Issue 3, 848-857, March 2003

Isoprenylcysteine Carboxyl Methyltransferase Activity Modulates Endothelial Cell Apoptosis

Kristina Kramer,^* Elizabeth O. Harrington,^* Qing Lu, Robert Bellas, Julie Newton, Kerri L. Sheahan, and Sharon Rounds

Pulmonary Vascular Biology Laboratory, Providence Veterans Affairs Medical Center, Brown Medical School, Providence, Rhode Island 02908

Extracellular ATP, adenosine (Ado), and adenosine plus homocysteine (Ado/HC) cause apoptosis of cultured pulmonary artery endothelial cells through the enhanced formation of intracellular S-adenosylhomocysteine and disruption of focal adhesion complexes. Because an increased intracellular ratio of S-adenosylhomocysteine/S-adenosylmethionine favors inhibition of methylation, we hypothesized that Ado/HC might act by inhibition of isoprenylcysteine-O-carboxyl methyltransferase (ICMT). We found that N-acetyl-S-geranylgeranyl-L-cysteine (AGGC) and N-acetyl-S-farnesyl-L-cysteine (AFC), which inhibit ICMT by competing with endogenous substrates for methylation, caused apoptosis. Transient overexpression of ICMT inhibited apoptosis caused by Ado/HC, UV light exposure, or tumor necrosis factor-. Because the small GTPase, Ras, is a substrate for ICMT and may modulate apoptosis, we also hypothesized that inhibition of ICMT with Ado/HC or AGGC might cause endothelial apoptosis by altering Ras activation. We found that ICMT inhibition decreased Ras methylation and activity and the activation of the downstream signaling molecules Akt, ERK-1, and ERK-2. Furthermore, overexpression of wild-type or dominant active H-Ras blocked Ado/HC-induced apoptosis. These findings suggest that inhibition of ICMT causes endothelial cell apoptosis by attenuation of Ras GTPase methylation and activation and its downstream antiapoptotic signaling pathway.

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^* These authors contributed equally to this work.

Corresponding author. E-mail address: Sharon_Rounds{at}brown.edu.

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Molecular Biology of the Cell
Vol. 14, 848-857, March 2003
Copyright © 2003 by The American Society for Cell Biology

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