PMID:15837622

Citation	Lackner, MR, Kindt, RM, Carroll, PM, Brown, K, Cancilla, MR, Chen, C, de Silva, H, Franke, Y, Guan, B, Heuer, T, Hung, T, Keegan, K, Lee, JM, Manne, V, O'Brien, C, Parry, D, Perez-Villar, JJ, Reddy, RK, Xiao, H, Zhan, H, Cockett, M, Plowman, G, Fitzgerald, K, Costa, M and Ross-Macdonald, P (2005) Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors. Cancer Cell 7:325-36
Abstract	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.
Links	PubMed Online version:10.1016/j.ccr.2005.03.024
Keywords	Alkyl and Aryl Transferases/antagonists & inhibitors; Alkyl and Aryl Transferases/metabolism; Alkyl and Aryl Transferases/physiology; Animals; Antineoplastic Agents/pharmacology; Apoptosis/drug effects; Apoptosis/genetics; Apoptosis/physiology; Caenorhabditis elegans/drug effects; Caenorhabditis elegans/enzymology; Caenorhabditis elegans/genetics; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/physiology; Calcium-Binding Proteins/genetics; Calcium-Binding Proteins/physiology; Caspases/genetics; Caspases/metabolism; Caspases/physiology; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors/pharmacology; Gene Expression/genetics; Germ Cells/drug effects; Humans; Mutagenesis/genetics; Neoplasms/enzymology; Neoplasms/genetics; Protein Prenylation/drug effects; RNA Interference; RNA, Double-Stranded/genetics; RNA, Small Interfering/genetics; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Protein p53/physiology; rab GTP-Binding Proteins/genetics
edit table

Annotations

Gene product	Qualifier	GO ID	GO term name	Evidence Code	with/from	Aspect	Notes	Status
edit table

References

See Help:References for how to manage references in GONUTS.