IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis
IL-7Rα deficiency in p53null mice exacerbates thymocyte telomere erosion and lymphomagenesis
复制标题
DOI：
10.1038/cdd.2011.203
复制
发表时间：
2012-07-01
影响因子：
12.4
通讯作者：
Cui, Y.
中科院分区：
文献类型：
--
作者：
Kibe, R.;Zhang, S.;Cui, Y.
白细胞介素-7 （IL-7）是t细胞生存必需的细胞因子。IL-7受体（IL-7R α）缺乏严重影响t细胞的发育，导致大量细胞凋亡。我们假设IL-7R α (null)诱导的细胞凋亡部分与p53活性升高有关。为了研究IL-7/IL-7R α信号通路与p53通路的遗传关联，我们构建了IL-7R α (null)p53(null) （DKO）小鼠。DKO小鼠表现出发育中的T细胞凋亡显著减少，胸腺淋巴瘤发生增强，伴有端粒侵蚀和染色体异常加剧，包括染色体复制、断裂和易位。特别是，在DKO胸腺淋巴瘤中，端粒染色体在着丝粒区融合，端粒在融合部位完全丢失的Robertsonian易位经常发生。细胞和分子研究表明，IL-7/IL-7R α信号的退出减少了端粒保护复合物庇护蛋白亚基端粒1 （POT1）的保护蛋白合成，导致端粒侵蚀和p53通路的激活。阻断IL-7依赖性p53（null）细胞中的IL-7/IL-7R α信号会降低POT1的表达，导致端粒和染色体异常，类似于在DKO淋巴瘤中观察到的情况。该研究强调了IL-7/IL-7R α在t细胞发育过程中通过POT1表达调节端粒完整性的新功能，并为细胞因子介导的生存信号和t细胞淋巴瘤发生提供了新的见解。细胞死亡与分化（2012）19,1139-1151；doi: 10.1038 / cdd.2011.203;2012年1月27日在线发布
Interleukin-7 (IL-7) is an essential T-cell survival cytokine. IL-7 receptor (IL-7R alpha) deficiency severely impairs T-cell development due to substantial apoptosis. We hypothesized that IL-7R alpha(null)-induced apoptosis is partially contributed by an elevated p53 activity. To investigate the genetic association of IL-7/IL-7R alpha signaling with the p53 pathway, we generated IL-7R alpha(null)p53(null) (DKO) mice. DKO mice exhibited a marked reduction of apoptosis in developing T cells and an augmented thymic lymphomagenesis with telomere erosions and exacerbated chromosomal anomalies, including chromosome duplications, breaks, and translocations. In particular, Robertsonian translocations, in which telocentric chromosomes fuse at the centromeric region, and a complete loss of telomeres at the fusion site occurred frequently in DKO thymic lymphomas. Cellular and molecular investigations revealed that IL-7/IL-7R alpha signaling withdrawal diminished the protein synthesis of protection of telomere 1 (POT1), a subunit of telomere protective complex shelterin, leading to telomere erosion and the activation of the p53 pathway. Blockade of IL-7/IL-7R alpha signaling in IL-7-dependent p53(null) cells reduced POT1 expression and caused telomere and chromosome abnormalities similar to those observed in DKO lymphomas. This study underscores a novel function of IL-7/IL-7R alpha during T-cell development in regulating telomere integrity via POT1 expression and provides new insights into cytokine-mediated survival signals and T-cell lymphomagenesis. Cell Death and Differentiation (2012) 19, 1139-1151; doi: 10.1038/cdd.2011.203; published online 27 January 2012