Oncogenic mechanisms of Evi-1 protein.
Although Evi-1 is thought to promote growth or block differentiation in some cell types, its biological functions have not been elucidated. To explore the mechanisms underlying Evi-1-induced oncogenesis, we investigated whether Evi-1 affects the signaling of transforming growth factor beta (TGF-beta), which inhibits proliferation of a wide range of cell types and is one of the most studied growth regulatory factors. We demonstrated that Evi-1 represses TGF-beta signaling and antagonizes its growth-inhibitory effects. Two separate regions of Evi-1 are responsible for this repression, one of which is the first zinc-finger domain. Through this domain, Evi-1 physically interacts with Smad3, an intracellular mediator of TGF-beta signaling, thereby suppressing the transcriptional activity of Smad3. These results define a novel function of Evi-1 as a repressor of signaling components of TGF-beta. We also demonstrated that Evi-1 represses Smad-induced transcriptional activation by recruiting CtBP as a corepressor. Evi-1 associates with CtBP1 through one of the CtBP-binding consensus motifs within the region from amino acid 544 to 607, and this association is required for the efficient inhibition of TGF-beta signaling. A specific histone deacetylase (HDAc) inhibitor, trichostatin A (TSA), alleviates Evi-1-mediated repression of TGF-beta signaling, suggesting that HDAc is involved in transcriptional repression by Evi-1. This identifies a novel function of Evi-1 as a member of corepressor complexes and suggests that aberrant recruitment of corepressors is one of the mechanisms involved in Evi-1-induced leukemogenesis. These results indicate that specific HDAc inhibitors may be useful in the treatment of Evi-1-induced neoplastic tumors, including myeloid leukemias.
Hirai
H
H
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Hongo, Japan. hhirai-tky@umin.ac.jp
Izutsu
K
K
Kurokawa
M
M
Mitani
K
K
D000818:Animals; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D011519:Proto-Oncogenes; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D016335:Zinc Fingers / Q000502:physiology
D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta