Disease relevance of ICMT

• In this paper, we report on modulation of pcCMT activity in retinoic acid (RA)-treated SH-SY5Y neuroblastoma cells using N-acetyl-S-farnesyl-L-cysteine (AFC) as artificial methyl acceptor [1].

High impact information on ICMT

• Fibroblasts harboring a floxed Icmt allele and expressing activated K-Ras (K-Ras-Icmt(flx/flx)) were treated with Cre-adenovirus, producing K-Ras-Icmt(Delta/Delta) fibroblasts [2].
• Inactivation of Icmt inhibited cell growth and K-Ras-induced oncogenic transformation, both in soft agar assays and in a nude mice model [2].
• Whereas cells expressing wild-type levels of Icmt are inhibited by methotrexate, stable expression of myristoylated H-Ras, which does not require carboxyl methylation for membrane attachment (7), confers resistance to methotrexate [3].
• Additionally, cells lacking Icmt are highly resistant to methotrexate [3].
• Because carboxyl methylation of Ras is important for proper plasma membrane localization and function (6), we investigated the role of Icmt in the antiproliferative effect of methotrexate [3].

Biological context of ICMT

• To determine the consequences of ICMT inhibition, we investigated the effect of AFC on p38 mitogen-activated protein (MAP) kinase phosphorylation, which is downstream of Rac1 [4].
• 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 [5].
• Transient overexpression of ICMT inhibited apoptosis caused by Ado/HC, UV light exposure, or tumor necrosis factor-alpha [5].
• Notably, four of the five loss-of-function mutations arising from random mutagenesis alter residues that are highly conserved among the ICMT family [6].
• This region is similar among all ICMT family members, two phospholipid methyltransferases, several ergosterol biosynthetic enzymes, and a group of bacterial open reading frames of unknown function [6].

Anatomical context of ICMT

• 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 [5].
• Mammalian pcCMT was not expressed at the plasma membrane but rather restricted to the endoplasmic reticulum [7].
• Mammalian prenylcysteine carboxyl methyltransferase is in the endoplasmic reticulum [7].
• An anti-pcCMT antiserum detected a 33-kDa protein in myeloid cell membranes [7].
• However, endogenous geranylgeranylated non-methylated Rab-CAAX and Rab-CXC proteins were significantly redistributed to the cytosol at steady-state levels and redistribution correlates with higher affinity of RabGDI for non-methylated Rabs in Icmt-deficient cells [8].

Associations of ICMT with chemical compounds

• Ras and Rho proteins possess a C-terminal CAAX motif (C is cysteine, A is usually an aliphatic residue, and X is any amino acid), in which the cysteine is prenylated, followed by proteolytic cleavage of the AAX peptide and carboxyl methylation by the Rce1 CAAX protease and Icmt methyltransferase, respectively [8].
• A potential mechanism for the detrimental effects of homocysteine is cellular hypomethylation from an increase in S-adenosylhomocysteine (5), an inhibitor of methyltransferases including isoprenylcysteine carboxyl methyltransferase (Icmt) [3].

Other interactions of ICMT

• Role of isoprenylcysteine carboxyl methyltransferase in tumor necrosis factor-alpha stimulation of expression of vascular cell adhesion molecule-1 in endothelial cells [9].
• Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells [9].
• 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 [9].
• Quantitative real-time reverse transcription-PCR analyses were performed for the MGC4399, ICMT and RPL18 genes and confirmed the microarray findings [10].

Analytical, diagnostic and therapeutic context of ICMT

• The ICMT (International Center for Medical Technologies) Museum for Artificial Organs (Museum) was completed after phase I, II, and III expansions of the exhibit booths, which were made over the last two years [11].

References