Decreased Mdm2 expression inhibits tumor development and extends survival independent of Arf and dependent on p53.
Decreased Mdm2 expression inhibits tumor development and extends survival independent of Arf and dependent on p53.
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DOI：
10.1371/journal.pone.0046148
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Boyd K
中科院分区：
文献类型：
--
作者：
Eischen CM;Boyd K
Arf-Mdm 2-p53肿瘤抑制通路的失活是肿瘤发生的必要事件。Arf控制Mdm 2，Mdm 2反过来调节p53，但Arf和Mdm 2也具有影响肿瘤发展的p53非依赖性功能。此外，癌基因诱导的肿瘤发生的抑制依赖于Arf和p53，但在没有明显的癌基因过表达的情况下启动的肿瘤发展中Arf和p53的要求以及Mdm 2在此过程中的作用仍不清楚。在一系列的遗传实验中，在小鼠与定义的缺陷，在Arf，Mdm 2和/或p53，我们显示Mdm 2单倍不足显着延迟肿瘤发生的小鼠缺乏Arf和p53。Mdm 2杂合性显着抑制肿瘤的发展，在没有Arf的情况下，和Myc癌基因驱动的癌症相反，这种肿瘤发生的延迟不能与Arf的一个等位基因的存在下获救。值得注意的是，Mdm 2单倍抑制阻断了由p53杂合性引起的Arf缺陷小鼠中的加速肿瘤发展。然而，无论Arf状态如何，肿瘤发生在缺乏p53两个等位基因的Mdm 2杂合子小鼠中均未受到抑制。令人惊讶的是，在p53缺失小鼠中，Arf的缺失加速了肿瘤的发展。肿瘤谱主要由Arf和p53状态决定，Mdm 2单倍不足仅适度改变某些基因型中的肿瘤类型，而不是出现的原发性肿瘤的数量。因此，Mdm 2单倍不足对肿瘤潜伏期的显著影响独立于Arf，并且需要至少一个p53等位基因，并且Mdm 2缺陷对所发展的肿瘤类型的影响较小。这些数据还表明，在Arf和p53基因中存在通常加速肿瘤发生的多个遗传事件的情况下，Mdm 2水平降低具有保护作用。
Inactivation of the Arf-Mdm2-p53 tumor suppressor pathway is a necessary event for tumorigenesis. Arf controls Mdm2, which in turn regulates p53, but Arf and Mdm2 also have p53-independent functions that affect tumor development. Moreover, inhibition of oncogene-induced tumorigenesis relies on Arf and p53, but the requirements of Arf and p53 in tumor development initiated in the absence of overt oncogene overexpression and the role of Mdm2 in this process remain unclear. In a series of genetic experiments in mice with defined deficiencies in Arf, Mdm2 and/or p53, we show Mdm2 haploinsufficiency significantly delayed tumorigenesis in mice deficient in Arf and p53. Mdm2 heterozygosity significantly inhibited tumor development in the absence of Arf, and in contrast to Myc oncogene-driven cancer, this delay in tumorigenesis could not be rescued with the presence of one allele of Arf. Notably, Mdm2 haploinsufficieny blocked the accelerated tumor development in Arf deficient mice caused by p53 heterozygosity. However, tumorigenesis was not inhibited in Mdm2 heterozygous mice lacking both alleles of p53 regardless of Arf status. Surprisingly, loss of Arf accelerated tumor development in p53-null mice. Tumor spectrum was largely dictated by Arf and p53 status with Mdm2 haploinsufficiency only modestly altering the tumor type in some of the genotypes and not the number of primary tumors that arose. Therefore, the significant effects of Mdm2 haploinsufficiency on tumor latency were independent of Arf and required at least one allele of p53, and an Mdm2 deficiency had minor effects on the types of tumors that developed. These data also demonstrate that decreased levels of Mdm2 are protective in the presence of multiple genetic events in Arf and p53 genes that normally accelerate tumorigenesis.
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影响因子：
8
作者：
Eischen, CM;Alt, JR;Wang, P
通讯作者：
Wang, P
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
DOI：
10.1073/pnas.93.24.14106
发表时间：
1996-11-26
影响因子：
11.1
作者：
Jones, SN;Sands, AT;Bradley, A
通讯作者：
Bradley, A
影响因子：
8
作者：
Wang, P.;Greiner, T. C.;Eischen, C. M.
通讯作者：
Eischen, C. M.
影响因子：
10.5
作者：
Weber, JD;Jeffers, JR;Zambetti, GP
通讯作者：
Zambetti, GP