The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 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 culture and in primary retrovirus-induced thymomas and encodes a nuclear, sequence-specific DNA-binding protein. Here we show that Gfi-1 is a position- and orientation-independent active transcriptional repressor, whose activity depends on a 20-amino-acid N-terminal repressor domain, coincident with a nuclear localization motif. The sequence of the Gfi-1 repressor domain is related to the sequence of the repressor domain of Gfi-1B, a Gfi-1-related protein, and to sequences at the N termini of the insulinoma-associated protein, IA-1, the homeobox protein Gsh-1, and the vertebrate but not the Drosophila members of the Snail-Slug protein family (Snail/Gfi-1, SNAG domain). Although not functionally characterized, these SNAG-related sequences are also likely to mediate transcriptional repression. Therefore, the Gfi-1 SNAG domain may be the prototype of a novel family of evolutionarily conserved repressor domains that operate in multiple cell lineages. Gfi-1 overexpression in IL-2-dependent T-cell lines allows the cells to escape from the G1 arrest induced by IL-2 withdrawal. Since a single point mutation in the SNAG domain (P2A) inhibits both the Gfi-1-mediated transcriptional repression and the G1 arrest induced by IL-2 starvation, we conclude that the latter depends on the repressor activity of the SNAG domain. Induction of Gfi-1 may therefore contribute to T-cell activation and tumor progression by repressing the expression of genes that inhibit cellular proliferation.
Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
H L
HL
Grimes
T O
TO
Chan
P A
PA
Zweidler-McKay
B
B
Tong
P N
PN
Tsichlis
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002645:Chickens; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis; D016384:Consensus Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D004330:Drosophila; D016193:G1 Phase; D017930:Genes, Reporter; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D012190:Retroviridae; D017386:Sequence Homology, Amino Acid; D000071250:Snail Family Transcription Factors; D012908:Snails; D013945:Thymoma; D013953:Thymus Neoplasms; D014157:Transcription Factors; D014162:Transfection; D014714:Vertebrates; D014981:Xenopus; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C498275:GFI1 protein, human; C079873:Gfi1 protein, mouse; C498276:Gfi1 protein, rat; D007376:Interleukin-2; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011994:Recombinant Proteins; D012097:Repressor Proteins; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; C000604450:Snai2 protein, rat; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C000604451:sna protein, Drosophila; D015500:Chloramphenicol O-Acetyltransferase