Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP
Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP
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DOI：
10.1038/sj.onc.1208754
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发表时间：
2005-09-08
期刊：
影响因子：
8
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Nitta, E;Izutsu, K;Hirai, H
Evi-1是与造血细胞的白血病转化有关的转录因子。两种不同的替代形式，Evi-1a和Evi-1c，是由EVI-1基因产生的。尽管Evi-1a被广泛认为是一种癌蛋白，但Evi-1c在白血病发生中的作用迄今尚未阐明，Evi-1c在Evi-1a的氨基末端具有额外的PR结构域。转录因子的异常寡聚化最近已成为激活其在造血系统恶性肿瘤中的致癌潜力的普遍机制。在这里，为了研究Evi-1介导的肿瘤发生的机制，我们研究了Evi-1蛋白形成的寡聚复合物。我们发现，Evi-1a形成的同源寡聚体，而Evi-1c只存在于哺乳动物细胞中的单体。值得注意的是，Evi-1c已经失去了与CtBP相互作用的能力，CtBP是一种与Evi-1a相关的转录辅抑制因子。因此，Evi-1c抑制转化生长因子-β（TGF-β）信号传导的能力被显著废除。这些结果确定了PR结构域调节转录因子寡聚化的新功能，并表明同源寡聚化可能在Evi-1蛋白的辅阻遏物募集中发挥关键作用。此外，我们发现，嵌合癌蛋白急性髓细胞白血病（AML）1-Evi-1，产生于t（3; 21）白血病，也形成同源寡聚体和异源寡聚体Evi-1a，而它不与Evi-1c相互作用。与结果一致的是，AML 1-Evi-1对TGF-β的抑制被Evi-1a显著增强，而Evi-1c的存在几乎不影响TGF-β的抑制。这些结果表明，寡聚化可能有助于Evi-1蛋白的致癌潜力。
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-beta ( TGF-beta) 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-beta 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.