EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma.
EWS/FLI and its downstream target NR0B1 interact directly to modulate transcription and oncogenesis in Ewing's sarcoma.
复制标题
DOI：
10.1158/0008-5472.can-09-1540
复制
发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Lessnick SL
中科院分区：
文献类型：
--
作者：
Kinsey M;Smith R;Iyer AK;McCabe ER;Lessnick SL
大多数尤因氏肉瘤都存在染色体易位，编码 EWS 和 ETS 家族成员之间的融合。最常见的融合体 EWS/FLI 由 EWSR1 衍生的强转录激活结构域组成，该结构域与 FLI1 包含 DNA 结合结构域的部分在框架内融合。 EWS/FLI 作为异常转录因子来调节介导尤文氏肉瘤致癌表型的基因。这些调节基因之一，NR0B1，编码一种共阻遏蛋白，并且可能在肿瘤发生中发挥转录作用。然而，尤文肉瘤中 NR0B1 调节的基因及其相互作用的转录因子在很大程度上尚不清楚。我们使用转录分析和染色质免疫沉淀来识别受 NR0B1 调节的基因，并将这些数据与 EWS/FLI 的类似数据进行比较。虽然转录谱如预期重叠，但我们还发现 NR0B1 和 EWS/FLI 的全基因组定位也重叠，表明它们协调调节一些基因。进一步分析表明 NR0B1 和 EWS/FLI 存在物理相互作用。这种蛋白质-蛋白质相互作用可能与尤文氏肉瘤的发展有关，因为破坏这种相互作用的 NR0B1 突变会产生转录后果，并且还会消除致癌转化。综上所述，这些数据表明 EWS/FLI 和 NR0B1 在物理上相互作用，协调调节基因表达，并介导尤文肉瘤的转化表型。
Most Ewing's sarcomas harbor chromosomal translocations that encode fusions between EWS and ETS family members. The most common fusion, EWS/FLI, consists of an EWSR1-derived strong transcriptional activation domain fused, in frame, to the DNA binding domain-containing portion of FLI1. EWS/FLI functions as an aberrant transcription factor to regulate genes that mediate the oncogenic phenotype of Ewing's sarcoma. One of these regulated genes, NR0B1, encodes a co-repressor protein, and likely plays a transcriptional role in tumorigenesis. However, the genes that NR0B1 regulates and the transcription factors it interacts with in Ewing's sarcoma are largely unknown. We used transcriptional profiling and chromatin immunoprecipitation to identify genes that are regulated by NR0B1, and compared these data to similar data for EWS/FLI. While the transcriptional profile overlapped as expected, we also found that the genome-wide localization of NR0B1and EWS/FLI overlapped as well, suggesting that they regulate some genes coordinately. Further analysis revealed that NR0B1 and EWS/FLI physically interact. This protein-protein interaction is likely to be relevant for Ewing's sarcoma development because mutations in NR0B1 that disrupt the interaction have transcriptional consequences and also abrogate oncogenic transformation. Taken together, these data suggest that EWS/FLI and NR0B1 physically interact, coordinately modulate gene expression, and mediate the transformed phenotype of Ewing's sarcoma.