TXNIP Maintains the Hematopoietic Cell Pool by Switching the Function of p53 under Oxidative Stress
TXNIP Maintains the Hematopoietic Cell Pool by Switching the Function of p53 under Oxidative Stress
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DOI：
10.1016/j.cmet.2013.06.002
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发表时间：
2013-07-02
期刊：
影响因子：
29
通讯作者：
Choi, Inpyo
中科院分区：
文献类型：
--
作者：
Jung, Haiyoung;Kim, Mi Jeong;Choi, Inpyo
活性氧簇(ROS)是决定造血干细胞(HSCs)命运和造血的关键因素。硫氧还蛋白相互作用蛋白(TXNIP)是一种已知的细胞内ROS调节因子，由氧化应激诱导。TXNIP(-/-)老龄小鼠的造血细胞中ROS水平升高，造血细胞数量减少。TXNIP的缺失导致小鼠在氧化应激下的存活率显著降低。TXNIP通过干扰P53-小鼠双分钟2(MDM2)的相互作用和增加P53的转录活性来直接调节P53蛋白。TXNIP(-/-)小鼠表现出P53诱导的抗氧化基因下调。将TXNIP或P53导入TXNIP(-/-)骨髓细胞可以挽救小鼠氧化应激后的HSC频率，并极大地提高小鼠的存活率。综上所述，这些数据表明TXNIP是P53的调节者，并在氧化应激过程中通过调节细胞内ROS在维持造血细胞中发挥关键作用。
Reactive oxygen species (ROS) are critical determinants of the fate of hematopoietic stem cells (HSCs) and hematopoiesis. Thioredoxin-interacting protein (TXNIP), which is induced by oxidative stress, is a known regulator of intracellular ROS. Txnip(-/-) old mice exhibited elevated ROS levels in hematopoietic cells and showed a reduction in hematopoietic cell population. Loss of TXNIP led to a dramatic reduction of mouse survival under oxidative stress. TXNIP directly regulated p53 protein by interfering with p53- mouse double minute 2 (MDM2) interactions and increasing p53 transcriptional activity. Txnip(-/-) mice showed downregulation of the antioxidant genes induced by p53. Introduction of TXNIP or p53 into Txnip(-/-) bone marrow cells rescued the HSC frequency and greatly increased survival in mice following oxidative stress. Overall, these data indicate that TXNIP is a regulator of p53 and plays a pivotal role in the maintenance of the hematopoietic cells by regulating intracellular ROS during oxidative stress.