Author/Authors :
Lackner، نويسنده , , Mark R. and Kindt، نويسنده , , Rachel M. and Carroll، نويسنده , , Pamela M. and Brown، نويسنده , , Katherine and Cancilla، نويسنده , , Michael R. and Chen، نويسنده , , Changyou and de Silva، نويسنده , , Heshani and Franke، نويسنده , , Yvonne and Guan، نويسنده , , Bo and Heuer، نويسنده , , Tim and Hung، نويسنده , , Tak and Keegan، نويسنده , , Kevin and Lee، نويسنده , , Jae Moon and Manne، نويسنده , , Veeraswamy and O’Brien، نويسنده , , Carol and Parry، نويسنده , , Dianne and Perez-Villar، نويسنده , , Juan J. and Reddy، نويسنده , , Rajashekar K. and Xiao، نويسنده , , Hong and Zhan، نويسنده , , Hangjun and Cockett، نويسنده , , Mark and Plowman، نويسنده , , Greg and Fitzgerald، نويسنده , , Kevin D. Costa، نويسنده , , Michael and Ross-Macdonald، نويسنده , , Petra، نويسنده ,
Abstract :
Summary
ical 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.
