Title |
Oncogenic mechanisms of Evi-1 protein
|
---|---|
Published in |
Cancer Chemotherapy and Pharmacology, July 2001
|
DOI | 10.1007/s002800100303 |
Pubmed ID | |
Authors |
Hisamaru Hirai, Koji Izutsu, Mineo Kurokawa, Kinuko Mitani |
Abstract |
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. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 22 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Master | 5 | 23% |
Student > Ph. D. Student | 4 | 18% |
Student > Bachelor | 3 | 14% |
Professor | 3 | 14% |
Researcher | 3 | 14% |
Other | 4 | 18% |
Readers by discipline | Count | As % |
---|---|---|
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Biochemistry, Genetics and Molecular Biology | 7 | 32% |
Immunology and Microbiology | 1 | 5% |
Medicine and Dentistry | 1 | 5% |
Chemistry | 1 | 5% |
Other | 0 | 0% |
Unknown | 2 | 9% |