Spi-1 and Fli-1 Directly Activate Common Target Genes Involved in Ribosome Biogenesis in Friend Erythroleukemic Cells
Spi-1 and Fli-1 Directly Activate Common Target Genes Involved in Ribosome Biogenesis in Friend Erythroleukemic Cells
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DOI：
10.1128/mcb.01435-08
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发表时间：
2009-05-15
影响因子：
5.3
通讯作者：
Morle, Francois
中科院分区：
文献类型：
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作者：
Juban, Gaetan;Giraud, Guillaume;Morle, Francois
Spi-1和Fli-1是Friend病毒诱导的小鼠红白血病中反复失调的ETS转录因子。由于它们共享相同的核心DNA结合位点，我们研究了它们是否可能通过共同的机制导致红白血病。使用诱导敲低，我们证明，Fli-1有助于增殖，生存和分化逮捕的红白血病细胞窝藏一个激活的Fli-1基因座。类似地，我们使用诱导型Fli-1敲除和六亚甲基双乙酰胺（HMBA）或小干扰RNA介导的Spi-1敲除来研究它们各自在含有活化的Spi-1基因座的红白血病细胞中的作用。在这些细胞中，Spi-1和Fli-1的简单或双重敲除有助于诱导增殖停滞和分化。转录组分析显示，几乎所有受Fli-1敲除和HMBA影响的转录物都以加性方式受到影响。在这些加性下调的转录本中，超过20%编码参与核糖体生物合成的蛋白质，并且保守的ETS结合位点存在于其基因启动子中。通过染色质免疫沉淀，我们证明了在Friend红白血病细胞中Spi-1和Fli-1在这些启动子上的关联。这些数据使我们提出，Spi-1，Fli-1，和可能的其他ETS转录因子的致癌性可能涉及他们的能力，刺激核糖体生物合成。
Spi-1 and Fli-1 are ETS transcription factors recurrently deregulated in mouse erythroleukemia induced by Friend viruses. Since they share the same core DNA binding site, we investigated whether they may contribute to erythroleukemia by common mechanisms. Using inducible knockdown, we demonstrated that Fli-1 contributes to proliferation, survival, and differentiation arrest of erythroleukemic cells harboring an activated fli-1 locus. Similarly, we used inducible Fli-1 knockdown and either hexamethylenebisacetamide (HMBA)- or small interfering RNA-mediated Spi-1 knockdown to investigate their respective contributions in erythroleukemic cells harboring an activated spi-1 locus. In these cells, simple or double knockdown of both Spi-1 and Fli-1 additively contributed to induce proliferation arrest and differentiation. Transcriptome profiling revealed that virtually all transcripts affected by both Fli-1 knockdown and HMBA are affected in an additive manner. Among these additively downregulated transcripts, more than 20% encode proteins involved in ribosome biogenesis, and conserved ETS binding sites are present in their gene promoters. Through chromatin immunoprecipitation, we demonstrated the association of Spi-1 and Fli-1 on these promoters in Friend erythroleukemic cells. These data lead us to propose that the oncogenicity of Spi-1, Fli-1, and possibly other ETS transcription factors may involve their ability to stimulate ribosome biogenesis.