No requirement for V(D)J recombination in p53-deficient thymic lymphoma
No requirement for V(D)J recombination in p53-deficient thymic lymphoma
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DOI：
10.1128/mcb.18.6.3495
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发表时间：
1998-06-01
影响因子：
5.3
通讯作者：
Van Dyke, T
中科院分区：
文献类型：
--
作者：
Liao, MJ;Zhang, XX;Van Dyke, T
p53肿瘤抑制因子响应于多种细胞应激信号而被激活，尽管触发肿瘤抑制的特定体内信号是未知的。在p53失活导致肿瘤发生的小鼠胸腺细胞中，一些观察结果表明T细胞受体（TCR）位点的V（D）J重组可以提供DNA损伤信号，触发p53依赖性凋亡和肿瘤抑制。p53的失活将允许V（D）J驱动的另外的癌基因的突变，促进肿瘤发生。在这里，我们表明，在胸腺细胞中具有p53缺陷并且不能进行V（D）J重组的小鼠在胸腺瘤的发展中没有受损。将增殖激活基因（RAG）缺陷引入p53（-/-）小鼠和TgT Delta N转基因小鼠中，该品系中100%的小鼠由于猴病毒40 T抗原变体对p53的胸腺细胞特异性失活而发生胸腺瘤。尽管观察到了一些延迟，但V（D）J重组与肿瘤发生无关，因为胸腺瘤的发生有或没有RAG-1或RAG-2基因。当通过重排TCR转基因的表达抑制V（D）J重组时，100%的TgT Delta N小鼠发展胸腺瘤，令人惊讶地具有减少的潜伏期。将RAG缺陷进一步引入这些小鼠对肿瘤发生的时间或频率没有影响。最后，核型和染色体彩绘分析表明，没有证据表明TCR基因易位在p53缺陷型胸腺瘤，虽然丰富的非整倍体，涉及某些染色体的频繁重复。因此，与目前的假设相反，这些研究表明，除了V（D）J重组以外的信号促进胸腺细胞中p53肿瘤抑制，并且肿瘤发生的机制与TCR易位癌基因激活不同。
The p53 tumor suppressor is activated in response to a variety of cellular stress signals, although specific in vivo signals that trigger tumor suppression are unknown. In mouse thymocytes, where p53 inactivation leads to tumorigenesis, several observations suggest that V(D)J recombination of T-cell receptor (TCR) loci could provide a DNA damage signal triggering p53-dependent apoptosis and tumor suppression. Inactivation of p53 would allow V(D)J driven mutation of additional cancer genes, facilitating tumorigenesis, Here, we show that mice with a p53 deficiency in thymocytes and unable to carry out V(D)J recombination are not impaired in the development of thymoma, Recombination-activating gene (RAG) deficiencies were introduced into both p53(-/-) mice and TgT Delta N transgenic mice, a strain in which 100% of the mice develop thymoma due to thymocyte-specific inactivation of p53 by a simian virus 40 T-antigen variant. V(D)J recombination was dispensable for tumorigenesis since thymomas developed with or without the RAG-1 or RAG-2 gene, although some delay was observed. When V(D)J recombination was suppressed by expression of rearranged TCR transgenes, 100% of the TgT Delta N mice developed thymoma, surprisingly with reduced latency. Further introduction of a RAG deficiency into these mice had no impact on the timing or frequency of tumorigenesis. Finally, karyotype and chromosome painting analyses showed no evidence for TCR gene translocations in p53-deficient thymomas, although abundant aneuploidy involving frequent duplication of certain chromosomes was present. Thus, contrary to the current hypothesis, these studies indicate that signals other than V(D)J recombination promote p53 tumor suppression in thymocytes and that the mechanism of tumorigenesis is distinct from TCR translocation oncogene activation.