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

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.

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Figure 1: TGFβ-mediated transcriptional responses are suppressed by Evi-1.
Figure 2: Constitutive expression of Evi-1 in Mv1Lu cells overcomes TGFβ-mediated growth inhibition.
Figure 3: Evi-1 associates with Smad3 through the first zinc-finger domain of Evi-1.
Figure 4: Contribution of Evi-1 domains to the repression of TGF-β and SMAD signalling.
Figure 5: Evi-1 acts as a nuclear inhibitor of Smad3.

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Acknowledgements

We thank J. Massagué for Smad1–Flag and Smad4–HA; J. L. Wrana for Smad2–Flag and the pCMV5 vector; R. Derynck for Smad3–Flag and Smad4-Flag; X.-F. Wang for p15P113–Luc; K.Miyazono for p3TP–Lux and TβRI TD; and K. Arai for pME18Sneo. This work was supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health and Welfare and from the Ministry of Education, Science, and Culture of Japan.

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Correspondence to Hisamaru Hirai.

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Kurokawa, M., Mitani, K., Irie, K. et al. The oncoprotein Evi-1 represses TGF-β signalling by inhibiting Smad3. Nature 394, 92–96 (1998). https://doi.org/10.1038/27945

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