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The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling
1Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Japan.
Abstract:
Evi-1 is a zinc finger nuclear protein whose inappropriate expression leads to leukemic transformation of hematopoietic cells in mice and humans. This was previously shown to block the antiproliferative effect of transforming growth factor beta (TGF-beta). Evi-1 represses TGF-beta signaling by direct interaction with Smad3 through its first zinc finger motif. Here, it is demonstrated that Evi-1 represses Smad-induced transcription by recruiting C-terminal binding protein (CtBP) as a corepressor. Evi-1 associates with CtBP1 through one of the consensus binding motifs, and this association is required for efficient inhibition of TGF-beta signaling. A specific inhibitor for histone deacetylase (HDAc) alleviates Evi-1-mediated repression of TGF-beta signaling, suggesting that HDAc is involved in the 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 for Evi-1-induced leukemogenesis.
Insights
Evi-1 protein, a key factor in leukemia, blocks anti-cancer signaling by recruiting corepressors like CtBP. Histone deacetylase inhibitors can reverse this repression, offering potential therapeutic insights.
Area of Science:
- Molecular Biology
- Cancer Research
- Hematopoiesis
Background:
- Evi-1 is a zinc finger protein implicated in leukemic transformation.
- Evi-1 inhibits the antiproliferative effects of transforming growth factor beta (TGF-beta).
- Evi-1 directly interacts with Smad3 to repress TGF-beta signaling.
Purpose of the Study:
- To elucidate the mechanism by which Evi-1 represses TGF-beta signaling.
- To identify corepressors involved in Evi-1-mediated transcriptional repression.
- To investigate the role of histone deacetylase (HDAc) in Evi-1 function.
Main Methods:
- Investigated Evi-1 interaction with Smad3 and C-terminal binding protein (CtBP).
- Assessed the impact of Evi-1/CtBP association on TGF-beta signaling.
- Utilized histone deacetylase (HDAc) inhibitors to evaluate their effect on Evi-1 repression.
Main Results:
- Evi-1 recruits CtBP as a corepressor to inhibit Smad-induced transcription.
- Association between Evi-1 and CtBP1 is crucial for blocking TGF-beta signaling.
- HDAc inhibitors partially reversed Evi-1-mediated repression of TGF-beta signaling.
Conclusions:
- Evi-1 functions as a component of corepressor complexes.
- Aberrant recruitment of corepressors by Evi-1 contributes to leukemogenesis.
- Targeting corepressor interactions or HDAc activity may offer therapeutic strategies for Evi-1-driven leukemias.