Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.
Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.
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DOI：
10.1371/journal.pone.0021165
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Laman H
中科院分区：
文献类型：
--
作者：
Lomonosov M;Meziane el K;Ye H;Nelson DE;Randle SJ;Laman H
Fbxo7是一种不寻常的F盒蛋白，其增强与Cdk6的D型细胞周期蛋白复合物的形成，但不增强与Cdk4或Cdk2的D型细胞周期蛋白复合物的形成，并且其过表达已被证明以Cdk6依赖的方式转化永生化成纤维细胞。在这里，我们提出了新的证据，在体外和体内的致癌潜力，这种调节蛋白在原代造血干细胞和祖细胞（HSPCs）。HSPC中Fbxo7表达的增加抑制了其体外集落形成能力，特别是降低了CD11b（Mac1）表达，这些作用依赖于完整的p53通路。此外，增加的Fbxo7水平增强了p53无效HSPC的增殖能力，当它们生长在降低浓度的干细胞因子。最后，用表达Fbxo7的p53无效但非野生型HSPC重建的辐照小鼠显示体内T细胞淋巴瘤的发生率统计学显著增加。这些数据表明，Fbxo7以p53依赖性方式负调控HSPC的增殖和分化，并且在p53不存在的情况下，Fbxo7表达可以促进T细胞淋巴瘤发生。
Fbxo7 is an unusual F box protein that augments D-type cyclin complex formation with Cdk6, but not Cdk4 or Cdk2, and its over-expression has been demonstrated to transform immortalised fibroblasts in a Cdk6-dependent manner. Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs). Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway. Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 null HSPCs when they were grown in reduced concentrations of stem cell factor. Finally, irradiated mice reconstituted with p53 null, but not wild-type, HSPCs expressing Fbxo7 showed a statistically significant increase in the incidence of T cell lymphoma in vivo. These data argue that Fbxo7 negatively regulates the proliferation and differentiation of HSPCs in a p53-dependent manner, and that in the absence of p53, Fbxo7 expression can promote T cell lymphomagenesis.
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