THE GFI-1 PROTOONCOPROTEIN REPRESSES BAX EXPRESSION AND INHIBITS T-CELL DEATH

The Gfi-1 protooncogene encodes a nuclear zinc-finger protein that car ries a novel repressor domain, SNAG, and functions as a position- and orientation-independent active transcriptional repressor, The Gfi-1 re pressor allows interleukin 2 (IL-2)-dependent T cells to escape G(1) a rrest induced by IL-2 withdrawal in culture and collaborates with c-my c and pim-1 for the induction of retrovirus-induced lymphomas in anima ls, Here we show that overexpression of Gfi-1 also inhibits cell death induced by cultivation of IL-2-dependent T-cell lines in IL-2-deficie nt media. Similarly, induction of Gfi-1 in primary thymocytes from mic e carrying a metal-inducible Gfi-1 transgene inhibits cell death induc ed by cultivation in vitro. The protein and mRNA levels of the proapop totic regulator Bax are down-regulated by Gfi-1 in both immortalized T -cell lines and primary transgenic thymocytes. The repression is direc t and depends on several Gfi-1-binding sites in the p53-inducible Bax promoter, In addition to Bax, Gfi-1 also represses Bak, another apopto sis-promoting member of the Bcl-2 gene family. Therefore, Gfi-1 mag in hibit apoptosis by means of its repression of multiple proapoptotic re gulators, The antiapoptotic properties of Gfi-1 provide a potential ex planation for its strong collaboration with c-myc during oncogenesis.