Lipopolysaccharide-induced NF-kappa B activation in mouse 70Z/3 pre-B lymphocytes is inhibited by mevinolin and 5'-methylthioadenosine: roles of protein isoprenylation and carboxyl methylation reactions.

Abstract

We show that both the lipopolysaccharide (LPS)-induced activation of NF-cB DNA binding and K gene expression are blocked by treating murine pre-B lymphocyte 70Z/3 cells with 5'-methylthioadenosine (MTA), an inhibitor of several S-adenosylmethionine-dependent methylation reactions. We further show that the LPS-induced incorporation of radioactivity from [methyl-3H]methionine into methyl ester-like linkages on a group of membrane polypeptides is also inhibited by MTA treatment, suggesting the involvement of protein methylation reactions in the LPS signal transduction pathway. We also find that NF-KcB and c gene activation in LPS-treated 70Z/3 cells is blocked by mevinolin, an inhibitor that prevents protein isoprenylation. Interestingly, mevinolin-treated cells also exhibited a marked reduction in the methylation of membrane proteins. Neither MTA nor mevinolin significantly inhibited NF-KB activation by phorbol myristate acetate, suggesting that these agents act early in signal transduction. These results provide the first evidence that carboxyl methylated and/or isoprenylated proteins play an essential role in the LPS-signaling pathway.

The Mammalian Immediate-early TIS21 Protein and the Leukemia-associated BTG1 Protein Interact with a Protein-arginine -Methyltransferase

“…Moreover this methylation is reversible by the action of a methyl esterase (Xie and Clarke, 1994b). Additionally, endotoxin treatment of B cells (Law et al, 1992) and nerve growth factor treatment of PC12 pheochromocytoma cells (Kujubu et al, 1993) cause an increase in membrane-associated protein methylation that is specifically inhibited by pretreatment with the protein methylation inhibitor 5Ј-methylthioadenosine.…”

The Predominant Protein-arginine Methyltransferase from Saccharomyces cerevisiae

“…Sensitivity of the Yeast and Mammalian Protein-arginine Methyltransferases to Inhibitors-We compared the yeast and mammalian protein-arginine methyltransferase fusion proteins for their ability to be inhibited by AdoMet analogs that have been used to study cellular methylation reactions (Kujubu et al, 1993;Law et al, 1992). We incubated each of the fusion proteins with 5Ј-methylthioadenosine and S-adenosyl-L-homocysteine using rmt1 soluble extract as a source of methylaccepting polypeptides.…”

EFA (9-β-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine

“…However, both MTA and 5Ј-deoxyadenosine have associated toxicities in normal cells in vitro as well as effects in vivo including coronary vasodilation. 19,[25][26][27][28][29][30] For this reason, the present study aims to synthesize and evaluate a potentially nontoxic MTAP substrate, 9-␤-D-erythrofuranosyladenine (EFA), 31 as a salvage agent for MTAP ϩ cells (Figure 1) to enhance the therapeutic index of L-alanosine.…”