Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development
Loss of one allele of ARF rescues Mdm2 haploinsufficiency effects on apoptosis and lymphoma development
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DOI：
10.1038/sj.onc.1208052
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发表时间：
2004-11-25
期刊：
影响因子：
8
通讯作者：
Wang, P
中科院分区：
文献类型：
--
作者：
Eischen, CM;Alt, JR;Wang, P
肿瘤抑制因子p19（ARF）抑制Mdm 2，从而限制p53的活性。复杂的反馈和控制机制调节ARF，Mdm 2和p53的相互作用。在这里，我们报告说，ARF单倍不足完全挽救了Mdm 2单倍不足对B细胞发育，存活和转化的p53依赖性影响。与Mdm 2（+/-）B细胞相反，ARF缺陷的Mdm 2（+/-）B细胞在生长和凋亡率以及p53激活方面与野生型B细胞相似。因此，Mdm 2（+/-）Emu-myc转基因小鼠中显著减少的B细胞数量在ARF（+/-）Mdm（2+/-）Emu-myc转基因小鼠中恢复到正常水平。此外，ARF（+/-）Mdm 2（+/-）Emu-myc转基因小鼠发生淋巴瘤的速率与野生型Emu-myc转基因小鼠相似，表明ARF一个等位基因的缺失挽救了Mdm 2（+/-）Emu-myc转基因小鼠中延长的淋巴瘤潜伏期。重要的是，在ARF（+/-）Mdm 2（+/-）Emu-myc转基因淋巴瘤中，p53以在野生型Emu-myc转基因淋巴瘤中观察到的频率失活。总的来说，这些结果支持一个模型，即Mdm 2和ARF的化学计量控制细胞凋亡和肿瘤的发展，这应该有显着的意义，在治疗恶性肿瘤，灭活ARF。
The tumor suppressor p19(ARF) inhibits Mdm2, which restricts the activity of p53. Complicated feedback and control mechanisms regulate ARF, Mdm2, and p53 interactions. Here we report that ARF haploinsufficiency completely rescued the p53-dependent effects of Mdm2 haploinsufficiency on B-cell development, survival, and transformation. In contrast to Mdm2(+/-) B cells, Mdm2(+/-) B cells deficient in ARF were similar to wild-type B cells in their rates of growth and apoptosis and activation of p53. Consequently, the profoundly reduced numbers of B cells in Mdm2(+/-) Emu-myc transgenic mice were restored to normal levels in ARF(+/-)Mdm(2+/-) Emu-myc transgenics. Additionally, ARF(+/-)Mdm2(+/-) Emu-myc transgenics developed lymphomas at rates analogous to those observed for wild-type Emu-myc transgenics, demonstrating that loss of one allele of ARF rescued the protracted lymphoma latency in Mdm2(+/-) Emu-myc transgenics. Importantly, in ARF(+/-)Mdm2(+/-) Emu-myc transgenic lymphomas, p53 was inactivated at the frequency observed in lymphomas of wild-type Emu-myc transgenics. Collectively, these results support a model whereby the stoichiometry of Mdm2 and ARF controls apoptosis and tumor development, which should have significant implications in the treatment of malignancies that have inactivated ARF.