DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model.
DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model.
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DOI：
10.1084/jem.20062453
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发表时间：
2007-06-11
影响因子：
15.3
通讯作者：
Zhu, Chengming
中科院分区：
文献类型：
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作者：
Van Nguyen, Thang;Puebla-Osorio, Nahum;Pang, Hui;Dujka, Melanie E;Zhu, Chengming
肿瘤抑制因子p53依赖的细胞凋亡在抑制肿瘤发生中起关键作用。先前，我们报道了V(D)J重组位点的DNA双链断裂（DSBs）在非同源末端连接（NHEJ）缺陷的p53缺陷小鼠的发育淋巴细胞中诱导基因组不稳定，从而导致快速淋巴瘤形成。为了测试p53依赖的细胞周期阻滞在体内无细胞凋亡的情况下抑制肿瘤发生的能力，我们将nhej缺陷小鼠与突变的p53R172P背景杂交；这些小鼠在诱导凋亡方面存在缺陷，但没有细胞周期阻滞。这些双突变小鼠比NHEJ/p53双突变小鼠存活时间更长，而且值得注意的是，它们完全没有肿瘤。我们在T细胞受体（TCR）位点检测到异常V(D)J重组相关DSBs的积累，以及突变型p53和细胞周期检查点蛋白p21的高表达水平，但未检测到凋亡蛋白p53上调的凋亡调节剂。此外，在胸腺细胞和骨髓细胞中均观察到大量衰老细胞。细胞遗传学研究显示这些淋巴样细胞存在整倍体和有限的染色体断裂。结果表明，在p53 - p21依赖通路中，通常具有高增殖潜力的前体淋巴细胞能够退出细胞周期并经历衰老；这足以抑制致瘤性染色体异常和抑制肿瘤发生。
Tumor suppressor p53-dependent apoptosis is critical in suppressing tumorigenesis. Previously, we reported that DNA double-strand breaks (DSBs) at the V(D)J recombination loci induced genomic instability in the developing lymphocytes of nonhomologous end-joining (NHEJ)–deficient, p53-deficient mice, which led to rapid lymphomagenesis. To test the ability of p53-dependent cell cycle arrest to suppress tumorigenesis in the absence of apoptosis in vivo, we crossbred NHEJ-deficient mice into a mutant p53R172P background; these mice have defects in apoptosis induction, but not cell cycle arrest. These double-mutant mice survived longer than NHEJ/p53 double-null mice and, remarkably, were completely tumor free. We detected accumulation of aberrant V(D)J recombination–related DSBs at the T cell receptor (TCR) locus, and high expression levels of both mutant p53 and cell cycle checkpoint protein p21, but not the apoptotic protein p53-upregulated modulator of apoptosis. In addition, a substantial number of senescent cells were observed among both thymocytes and bone marrow cells. Cytogenetic studies revealed euploidy and limited chromosomal breaks in these lymphoid cells. The results indicate that precursor lymphocytes, which normally possess a high proliferation potential, are able to withdraw from the cell cycle and undergo senescence in response to the persistence of DSBs in a p53–p21–dependent pathway; this is sufficient to inhibit oncogenic chromosomal abnormality and suppress tumorigenesis.