Decreased Mdm2 expression inhibits tumor development induced by loss of ARF
Decreased Mdm2 expression inhibits tumor development induced by loss of ARF
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DOI：
10.1038/sj.onc.1209411
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发表时间：
2006-06-22
期刊：
影响因子：
8
通讯作者：
Eischen, C. M.
中科院分区：
文献类型：
--
作者：
Wang, P.;Greiner, T. C.;Eischen, C. M.
肿瘤抑制因子p14/p19（ARF）调节Mdm 2，Mdm 2已知控制p53肿瘤抑制因子。在这里，我们报告说，在缺乏ARF的细胞中，Mdm 2的一个等位基因的丢失导致增殖率降低，染色体畸变减少，Ras诱导的转化受到抑制。此外，单倍不足的Mdm 2抑制自发性肿瘤的发展，在ARF无效的小鼠。值得注意的是，Mdm 2（+/-）ARF（-/-）小鼠的平均存活时间比Mdm 2（+/-）ARF（-/-）小鼠长6个月。在Mdm 2（+/-）ARF（-/-）小鼠中出现的肿瘤谱与仅缺乏ARF的小鼠中出现的肿瘤谱没有显著差异。然而，与仅ARF无效小鼠中出现的单一肿瘤类型相比，延长的肿瘤潜伏期允许在三分之一的Mdm 2（+/-）ARF（-/-）小鼠中出现多个原发性肿瘤。因此，Mdm 2水平的降低恢复了在转化过程中改变的关键细胞过程的调节，并且在没有ARF的情况下发生。我们的研究结果还表明，Mdm 2可以独立于ARF发挥作用，这意味着在缺乏ARF表达的肿瘤中靶向Mdm 2应该是一种有效的治疗方法。
The tumor suppressor p14/p19(ARF) regulates Mdm2, which is known for controlling the p53 tumor suppressor. Here we report that loss of one allele of Mdm2 in cells that lack ARF resulted in a decreased rate of proliferation, fewer chromosomal aberrations, and suppression of Ras-induced transformation. Moreover, a haploinsufficiency of Mdm2 inhibited spontaneous tumor development in ARF-null mice. Remarkably, Mdm2(+/-) ARF(-/-) mice survived an average of 6 months longer than Mdm2(+/-) ARF(-/-) mice. The spectrum of tumors that arose in Mdm2(+/-) ARF(-/-) mice did not significantly differ from those that developed in mice lacking only ARF. However, the extended tumor latency allowed for the emergence of multiple primary tumors in a third of the Mdm2(+/-) ARF(-/-) mice, as compared to the single tumor type that arose in ARF null only mic e. Therefore, a decrease in Mdm2 levels restored regulation of critical cellular processes that are altered during transformation and that occur in the absence of ARF. Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach.