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Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP

Oncogene volume 24, pages 6165–6173 (2005)Cite this article

Abstract

Evi-1 is a transcription factor that is implicated in leukemic transformation of hematopoietic cells. Two distinct alternative forms, Evi-1a and Evi-1c, are generated from the EVI-1 gene. Whereas Evi-1a is widely recognized as an oncoprotein, a role for Evi-1c, which has an additional PR domain in the amino-terminus of Evi-1a, in leukemogenesis, has not been elucidated thus far. Aberrant oligomerization of transcription factors has recently emerged as a prevalent mechanism for activating their oncogenic potential in hematopoietic malignancies. Here, to study the mechanisms that underlie Evi-1-mediated oncogenesis, we investigated formation of oligomeric complexes by the Evi-1 proteins. We show that Evi-1a forms homo-oligomers, whereas Evi-1c exclusively exists as a monomer in mammalian cells. Remarkably, Evi-1c has lost the ability to interact with CtBP, a transcriptional corepressor that associates with Evi-1a. As a consequence, the ability of Evi-1c to repress transforming growth factor-β (TGF-β) signaling is significantly abrogated. These results identify a novel function of a PR domain to regulate oligomerization of transcription factors and suggest that homo-oligomerization may play a critical role in corepressor recruitment by the Evi-1 proteins. In addition, we found that the chimeric oncoprotein acute myelocytic leukemia (AML)1-Evi-1, generated in t(3;21) leukemia, also forms homo-oligomers and hetero-oligomers with Evi-1a, while it did not interact with Evi-1c. Consistent with the results, repression of TGF-β by AML1-Evi-1 was significantly enhanced by Evi-1a, whereas it was hardly affected by the presence of Evi-1c. These results suggest that oligomerization may contribute to the oncogenic potential of Evi-1-containing proteins.

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Acknowledgements

We thank Norio Komatsu (Yamanashi Medical School) for providing the 293T cells. We also thank Kinuko Mitani (Dokkyo University school of Medicine) and other H. H's lab members for helpful discussions. This work was supported in part by a Grant-in Aid for Scientific Research from the Japan Society for the Promotion of Science, and by Health and Labor Sciences Research grants from the Ministry of Health, Labor and Welfare.

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  1. Hisamaru Hirai: Hisamaru Hirai passed away suddenly on August 23, 2003. His students, fellows and colleagues will greatly miss his energetic and nurturing leadership in the field of hematology. We dedicate this paper in his memory.

Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Eriko Nitta, Koji Izutsu, Yuko Yamaguchi, Yoichi Imai, Seishi Ogawa, Shigeru Chiba, Mineo Kurokawa & Hisamaru Hirai

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  1. Eriko Nitta
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  2. Koji Izutsu
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Correspondence to Mineo Kurokawa.

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Nitta, E., Izutsu, K., Yamaguchi, Y. et al. Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP. Oncogene 24, 6165–6173 (2005). https://doi.org/10.1038/sj.onc.1208754

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