Schmitt Clemens A, Fridman Jordan S, Yang Meng, Baranov Eugene, Hoffman Robert M, Lowe Scott W
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Cancer Cell. 2002 Apr;1(3):289-98. doi: 10.1016/s1535-6108(02)00047-8.
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.
尽管p53肿瘤抑制因子在众多影响细胞增殖和存活的过程中发挥作用，但目前仍不清楚p53的哪些功能对于肿瘤抑制至关重要，因此在肿瘤发生过程中会被选择淘汰。利用携带原发性、基因改造的myc驱动淋巴瘤的小鼠模型，我们发现通过Bcl2或显性负性caspase 9破坏p53下游的凋亡赋予了类似p53缺失的选择性优势，并完全减轻了淋巴瘤发生过程中使p53失活的压力。尽管具有类似p53缺失的侵袭性表型，但保留完整p53基因的凋亡缺陷型淋巴瘤并未表现出p53突变肿瘤特有的检查点缺陷和严重非整倍体。因此，凋亡是淋巴瘤发生过程中唯一被选择淘汰的p53功能，而缺陷的细胞周期检查点和非整倍体仅仅是p53缺失的副产物。
