Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
Tissue-specific differences of p53 inhibition by Mdm2 and Mdm4
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DOI：
10.1128/mcb.26.1.192-198.2006
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发表时间：
2006-01-01
影响因子：
5.3
通讯作者：
Lozano, G
中科院分区：
文献类型：
--
作者：
Grier, JD;Xiong, SB;Lozano, G
p53肿瘤抑制因子抑制增殖或启动凋亡的功能在肿瘤细胞中通常被废除。Mdm 2及其同源物Mdm 4是p53的关键抑制剂，通常在人类肿瘤中过表达。在小鼠中，Mdm2或Mdm4的缺失导致胚胎致死表型，其通过伴随的p53缺失而被完全拯救。为了研究Mdm 2和Mdm 4在时间和组织特异性方式中的作用，并确定这些抑制剂彼此之间的关系，我们产生了条件等位基因。我们删除了心肌细胞中的Mdm 2和Mdm 4，因为增殖和凋亡是心脏发育中的重要过程。心脏中缺乏Mdm 2的小鼠是胚胎致死的，并且在重组发生时显示出缺陷。在胚胎第13.5天，大量心肌细胞丢失，导致心力衰竭。这种表型通过p53的缺失而被完全拯救。心脏中缺乏Mdm 4的小鼠以正确的比例出生，并且看起来正常。我们的研究提供了第一个直接的证据表明，Mdm 2可以在Mdm 4的情况下发挥作用，以组织特异性的方式调节p53的活性。此外，Mdm 4不能补偿心脏发育中Mdm 2的损失。
The function of the p53 tumor suppressor to inhibit proliferation or initiate apoptosis is often abrogated in tumor cells. Mdm2 and its homolog, Mdm4, are critical inhibitors of p53 that are often overexpressed in human tumors. In mice, loss of Mdm2 or Mdm4 leads to embryonic lethal phenotypes that are completely rescued by concomitant loss of p53. To examine the role of Mdm2 and Mdm4 in a temporal and tissue-specific manner and to determine the relationships of these inhibitors to each other, we generated conditional alleles. We deleted Mdm2 and Mdm4 in cardiomyocytes, since proliferation and apoptosis are important processes in heart development. Mice lacking Mdm2 in the heart were embryonic lethal and showed defects at the time recombination occurred. A critical number of cardiomyocytes were lost by embryonic day 13.5, resulting in heart failure. This phenotype was completely rescued by deletion of p53. Mice lacking Mdm4 in the heart were born at the correct ratio and appeared to be normal. Our studies provide the first direct evidence that Mdm2 can function in the absence of Mdm4 to regulate p53 activity in a tissue-specific manner. Moreover, Mdm4 cannot compensate for the loss of Mdm2 in heart development.