Kraut N, Frampton J, McNagny K M, Graf T
Differentiation Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Genes Dev. 1994 Jan;8(1):33-44. doi: 10.1101/gad.8.1.33.
Earlier work demonstrated that the Myb-Ets fusion protein of E26 avian leukemia virus induces the proliferation of multipotent hematopoietic progenitors (MEPs). These progenitors differentiate spontaneously at low frequencies along the erythroid lineage, and following the introduction of kinase/ras-type oncogenes or treatment with TPA, they are induced to differentiate along the myelomonocytic and eosinophilic lineages. Here, we show that the ts1.1 mutant of E26 encodes an Ets DNA-binding domain that is both defective and thermolabile for binding of specific DNA sequences. Correlating with this, ts1.1 MEP colonies transformed at the permissive temperature exhibit elevated levels of erythroid cells and eosinophils, whereas at the nonpermissive temperature they are induced to differentiate along the erythroid and myelomonocytic lineages and, to a lesser extent, along the eosinophil lineage. Induction of the former two lineages cannot be separated by pulse shift experiments and is essentially completed 2.5 days after temperature shift. Our results indicate that the Ets portion of the Myb-Ets fusion protein inhibits the lineage commitment of multipotent hematopoietic progenitors, probably via binding to regulatory DNA sequences of specific target genes.
早期研究表明，E26禽白血病病毒的Myb-Ets融合蛋白可诱导多能造血祖细胞（MEP）增殖。这些祖细胞在低频下沿红系谱系自发分化，在引入激酶/ras型癌基因或用佛波酯（TPA）处理后，它们被诱导沿髓单核细胞系和嗜酸性粒细胞系分化。在此，我们表明E26的ts1.1突变体编码一个Ets DNA结合结构域，该结构域在结合特定DNA序列时存在缺陷且不耐热。与此相关的是，在允许温度下转化的ts1.1 MEP集落中，红系细胞和嗜酸性粒细胞水平升高，而在非允许温度下，它们被诱导沿红系和髓单核细胞系分化，在较小程度上沿嗜酸性粒细胞系分化。前两个谱系的诱导不能通过脉冲转移实验分开，并且在温度转移后2.5天基本完成。我们的结果表明，Myb-Ets融合蛋白的Ets部分可能通过与特定靶基因的调控DNA序列结合来抑制多能造血祖细胞的谱系定向分化。
