Dissecting p53 tumor suppressor functions in vivo
Dissecting p53 tumor suppressor functions in vivo
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DOI：
10.1016/s1535-6108(02)00047-8
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发表时间：
2002-04-01
期刊：
影响因子：
50.3
通讯作者：
Lowe, SW
中科院分区：
文献类型：
--
作者：
Schmitt, CA;Fridman, JS;Lowe, SW
尽管p53肿瘤抑制因子在影响细胞增殖和存活的众多过程中起作用，但目前尚不清楚哪些p53功能对肿瘤抑制至关重要，因此在肿瘤发展过程中被选中。通过小鼠原发性基因修饰myc驱动淋巴瘤模型，我们发现Bcl2或显性阴性caspase 9对p53下游细胞凋亡的破坏具有选择性优势，并完全减轻了淋巴瘤形成过程中p53失活的压力。尽管具有p53-null样侵袭性表型，保留完整p53基因的凋亡缺陷型淋巴瘤不会表现出p53突变肿瘤所特有的检查点缺陷和总体非整倍体。因此，在淋巴瘤发展过程中，细胞凋亡是p53唯一被选择反对的功能，而细胞周期检查点缺陷和非整倍体只是p53缺失的副产品。
Although the p53 tumor suppressor acts in a plethora of processes that influence cellular proliferation and survival, it remains unclear which p53 functions are essential for tumor suppression and, as a consequence, are selected against during tumor development. Using a mouse model harboring primary, genetically modified myc-driven lymphomas, we show that disruption of apoptosis downstream of p53 by Bcl2 or a dominant-negative caspase 9 confers-like p53 loss-a selective advantage, and completely alleviates pressure to inactivate p53 during lymphomagenesis. Despite their p53-null-like aggressive phenotype, apoptosis-defective lymphomas that retain intact p53 genes do not display the checkpoint defects and gross aneuploidy that are characteristic of p53 mutant tumors. Therefore, apoptosis is the only p53 function selected against during lymphoma development, whereas defective cell-cycle checkpoints and aneuploidy are mere byproducts of p53 loss.