Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors
2005; Cell Press; Volume: 7; Issue: 4 Linguagem: Inglês
10.1016/j.ccr.2005.03.024
ISSN1878-3686
AutoresMark R. Lackner, Rachel M. Kindt, Pamela M. Carroll, Katherine A. Brown, Michael R. Cancilla, Changyou Chen, Heshani de Silva, Yvonne Franke, Bo Guan, Tim Heuer, Tak Hung, Kevin Keegan, Jae Moon Lee, Veeraswamy Manne, Carol O’Brien, Dianne Parry, Juan J. Pérez‐Villar, Rajashekar K. Reddy, Hong Xiao, Hangjun Zhan, Mark I. Cockett, Gregory D. Plowman, Kevin Fitzgerald, Michael J. Costa, Petra Ross‐Macdonald,
Tópico(s)Protein Degradation and Inhibitors
ResumoSummary A chemical genetics approach identified a cellular target of several proapoptotic farnesyl transferase inhibitors (FTIs). Treatment with these FTIs caused p53-independent apoptosis in Caenorhabditis elegans , which was mimicked by knockdown of endosomal trafficking proteins, including Rab5, Rab7, the HOPS complex, and notably the enzyme Rab geranylgeranyl transferase (RabGGT). These FTIs were found to inhibit mammalian RabGGT with potencies that correlated with their proapoptotic activity. Knockdown of RabGGT induced apoptosis in mammalian cancer cell lines, and both RabGGT subunits were overexpressed in several tumor tissues. These findings validate RabGGT, and by extension endosomal function, as a therapeutically relevant target for modulation of apoptosis, and enhance our understanding of the mechanism of action of FTIs.
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