β-Catenin induces T-cell transformation by promoting genomic instability
β-Catenin induces T-cell transformation by promoting genomic instability
复制标题
DOI：
10.1073/pnas.1315752111
复制
发表时间：
2014-01-07
影响因子：
11.1
通讯作者：
Gounari, Fotini
中科院分区：
文献类型：
--
作者：
Dose, Marei;Emmanuel, Akinola Olumide;Gounari, Fotini
在癌症中β-连环蛋白的失调激活与基因组不稳定性相关。在胸腺细胞发育过程中，β-连环蛋白与T细胞特异性转录因子1（Tcf-1）共同激活转录。我们以前报道，靶向激活β-连环蛋白在胸腺细胞（CAT小鼠）诱导淋巴瘤，依赖于重组激活基因（RAG）和髓细胞瘤癌基因（Myc）的活动。在这里，我们表明，这些淋巴瘤有反复Tcra/Myc易位，导致非法RAG重组事件和类似的致癌易位先前描述的人类T-ALL。因此，我们使用CAT动物模型来获得对转化过程的机械见解。ChIP-seq分析揭示了Tcf-1和RAG 2之间的联系，表明这两种蛋白质在整个基因组中共享由三甲基化组蛋白-3赖氨酸-4（H3 K4 me 3）标记的结合位点，包括易位位点附近。预转化的CAT胸腺细胞在易位位点的DNA损伤增加，并表现出改变RAG诱导的DNA双链断裂的修复。这些细胞能够存活，尽管DNA损伤，因为激活β-连环蛋白促进抗凋亡基因表达谱。因此，活化的β-连环蛋白促进基因组不稳定性，其导致T细胞淋巴瘤，这是改变的双链断裂修复和具有受损DNA的胸腺细胞的存活增加的结果。
Deregulated activation of beta-catenin in cancer has been correlated with genomic instability. During thymocyte development, beta-catenin activates transcription in partnership with T-cell-specific transcription factor 1 (Tcf-1). We previously reported that targeted activation of beta-catenin in thymocytes (CAT mice) induces lymphomas that depend on recombination activating gene (RAG) and myelocytomatosis oncogene (Myc) activities. Here we show that these lymphomas have recurring Tcra/Myc translocations that resulted from illegitimate RAG recombination events and resembled oncogenic translocations previously described in human T-ALL. We therefore used the CAT animal model to obtain mechanistic insights into the transformation process. ChIP-seq analysis uncovered a link between Tcf-1 and RAG2 showing that the two proteins shared binding sites marked by trimethylated histone-3 lysine-4 (H3K4me3) throughout the genome, including near the translocation sites. Pretransformed CAT thymocytes had increased DNA damage at the translocating loci and showed altered repair of RAG-induced DNA double strand breaks. These cells were able to survive despite DNA damage because activated beta-catenin promoted an antiapoptosis gene expression profile. Thus, activated beta-catenin promotes genomic instability that leads to T-cell lymphomas as a consequence of altered double strand break repair and increased survival of thymocytes with damaged DNA.