Program in Genes and Development of The Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cell Stem Cell. 2010 Nov 5;7(5):606-17. doi: 10.1016/j.stem.2010.09.013.
Mdm2 is an E3 ubiquitin ligase that targets p53 for degradation. p53(515C) (encoding p53R172P) is a hypomorphic allele of p53 that rescues the embryonic lethality of Mdm2(-/-) mice. Mdm2(-/-) p53(515C/515C) mice, however, die by postnatal day 13 resulting from hematopoietic failure. Hematopoietic stem cells and progenitors of Mdm2(-/-) p53(515C/515C) mice were normal in fetal livers but were depleted in postnatal bone marrows. After birth, these mice had elevated reactive oxygen species (ROS) thus activating p53R172P. In the absence of Mdm2, stable p53R172P induced ROS and cell cycle arrest, senescence, and cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment and upon culturing of hematopoietic cells in methycellulose at 3% oxygen. p16 was also stabilized because of ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis.
Mdm2 是一种 E3 泛素连接酶，可将 p53 靶向降解。p53(515C)（编码 p53R172P）是 p53 的一个功能减弱等位基因，可挽救 Mdm2(-/-) 小鼠的胚胎致死性。然而，Mdm2(-/-) p53(515C/515C) 小鼠会因造血功能衰竭而在出生后第 13 天死亡。Mdm2(-/-) p53(515C/515C) 小鼠的造血干细胞和祖细胞在胎肝中正常，但在出生后的骨髓中耗尽。出生后，这些小鼠的活性氧（ROS）水平升高，从而激活 p53R172P。在没有 Mdm2 的情况下，稳定的 p53R172P 诱导 ROS 和细胞周期停滞、衰老和造血细胞死亡。用抗氧化剂治疗和在 3%氧气的甲基纤维素中培养造血细胞可以部分挽救这种表型。ROS 还稳定了 p16，其缺失增加了细胞周期并部分挽救了造血和生存。因此，Mdm2 是控制 ROS 诱导的 p53 水平以维持可持续造血所必需的。
