Fighting cancer by disrupting C-terminal methylation of signaling proteins
Steven Clarke, Fuyuhiko Tamanoi
Steven Clarke, Fuyuhiko Tamanoi
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):513-515. https://doi.org/10.1172/JCI21059.
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Commentary

Fighting cancer by disrupting C-terminal methylation of signaling proteins

Abstract

Protein methylation at the C-terminus of mammalian isoprenylated proteins has been implicated in membrane attachment, protein-protein interactions, and protein stability. A new paper describes surprising results: in the absence of methylation some target proteins have increased stability, whereas others have decreased stability. The decreased stability of the RhoA protein is correlated with an increased resistance to Ras-dependent transformation and suggests the basis for the development of a new approach to antitumor therapy .

Authors

Steven Clarke, Fuyuhiko Tamanoi

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Figure 1

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Modification pathway of proteins for isoprenylation/methylation and effe...
Modification pathway of proteins for isoprenylation/methylation and effects of inhibitors of each enzymatic step. Proteins ending with the CAAX motif undergo farnesylation in the cytosol. Subsequent removal of three C-terminal amino acids and C-terminal methylation are catalyzed by the endoplasmic reticulum–bound enzymes Rce1 and Icmt, respectively. Inhibition of Icmt leads to rapid turnover of RhoA, increase of p21Cip1, and cell cycle block. R115777, SCH66336, and BMS214662 are farnesyltransferase (Ftase) inhibitors, while farnesylcysteine and AdoHcy inhibit Icmt.