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

Evi-1 encodes a zinc-finger protein that may be involved in leukaemic transformation of haematopoietic cells(1-5). Evi-1 has two zinc-finger domains, one with seven repeats of a zinc-finger motif and one with three repeats(6), and it has characteristics of a transcriptional regulator(7,8). Although Evi-1 is thought to be able to promote growth and to block differentiation in some cell types(9-11), 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-beta (TGF-beta), one of the most studied growth-regulatory factors, which inhibits proliferation of a wide range of cell types(12). We show that Evi-1 represses TGF-beta signalling and antagonizes the growth-inhibitory effects of TGF-beta. 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-beta signalling(13), thereby suppressing the transcriptional activity of Smad3, These results define a new function of Evi-1 as a repressor of signalling through TGF-beta.