Protein prenylation is a post-translational modification that is essential for the transforming activity of many oncogenic proteins. This discovery triggered development of inhibitors against prenyltransferase enzymes. Despite the encouraging results in preclinical studies, these inhibitors failed to show efficacy as anti-cancer drugs in clinical trials, partly due to poor understanding of their mechanism of action. To measure the global effects of prenyltransferase inhibitors, we have metabolically labeled prenylated proteins in mammalian cells using alkyne-modified isoprenoid analogs in the presence and absence of prenyltransferase inhibitors. The resulting tagged proteins have been derivatized with two spectrally orthogonal dyes and visualized and quantified using differential gel electrophoresis (2D-DIGE); differentially labeled proteins have been identified using tandem mass spectrometry. These results have allowed us to identify several proteins that undergo altered levels of prenylation upon inhibitor treatment and hence should help to link the observed physiological effects of inhibitor treatment to their molecular targets.

Interrogating the prenylome using differential electrophoresis and metabolic labeling

243rd National Meeting (2012)

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