The oncoprotein Evi-1 represses TGF-β signalling by inhibiting Smad3

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Abstract
Evi-1 encodes a zinc-finger protein that may be involved in leukaemic transformation of haematopoietic cells1,2,3,4,5. Evi-1 has two zinc-finger domains, one with seven repeats of a zinc-finger motif and one with three repeats6, and it has characteristics of a transcriptional regulator7,8. Although Evi-1 is thought to be able to promote growth and to block differentiation in some cell types9,10,11, its biological functions are poorly understood. Here we study the mechanisms that underlie oncogenesis induced by Evi-1 by investigating whether Evi-1 perturbs signalling through transforming growth factor-β (TGF-β), one of the most studied growth-regulatory factors, which inhibits proliferation of a wide range of cell types12. We show that Evi-1 represses TGF-β signalling and antagonizes the growth-inhibitory effects of TGF-β. Two separate regions of Evi-1 are responsible for this repression; one of these regions is the first zinc-finger domain. Through this domain, Evi-1 interacts with Smad3, an intracellular mediator of TGF-β signalling13, thereby suppressing the transcriptional activity of Smad3. These results define a new function of Evi-1 as a repressor of signalling through TGF-β.