THE GFI-1 PROTO-ONCOPROTEIN CONTAINS A NOVEL TRANSCRIPTIONAL REPRESSOR DOMAIN, SNAG, AND INHIBITS G(1) ARREST INDUCED BY INTERLEUKIN-2 WITHDRAWAL

The Gfi-1 proto-oncogene is activated by provirus insertion in T-cell lymphoma lines selected for interleukin-2 (IL-2) independence in cultu re and in primary retrovirus-induced thymomas and encodes a nuclear se quence-specific DNA-binding protein, Here we show that Gfi-1 is a posi tion- and orientation-independent active transcriptional repressor, wh ose activity depends on a 20-amino-acid N-terminal repressor domain, c oincident with a nuclear localization motif. The sequence of the Gfi-1 repressor domain is related to the sequence of the repressor domain o f Gfi-1B, a Gfi-1-related protein, and to sequences at the N termini o f the insulinoma-associated protein, IA-1, the homeobox protein Gsh-1, and the vertebrate but not the Drosophila members of the Snail-Slug p rotein family (Snail/Gfi-1, SNAG domain), Although not functionally ch aracterized, these SNAG-related sequences are also likely to mediate t ranscriptional repression. Therefore, the Gfi-1 SNAG domain may be the prototype of a novel family of evolutionarily con:served repressor do mains that operate in multiple cell lineages, Gfi-1 overexpression in IL-2-dependent T-cell lines allows the cells to escape from the G(1) a rrest induced by IL-2 withdrawal. Since a single point mutation in the SNAG domain (P2A) inhibits both the Gfi-1-mediated transcriptional re pression and the G(1) arrest induced by IL-2 starvation, we conclude t hat the latter depends on the repressor activity of the SNAG domain. I nduction of Gfi-1 may therefore contribute to T-cell activation and tu mor progression by repressing the expression of genes that inhibit cel lular proliferation.