Massachusetts General Hospital Cancer Center, GRJ-904, 55 Fruit Street, Boston, MA 02114, USA.
Mol Cell Biol. 2011 Nov;31(21):4356-65. doi: 10.1128/MCB.05541-11. Epub 2011 Sep 6.
Exquisite control of the level and activity of p53 are required in order to preserve cellular homeostasis following DNA damage. How this regulation is integrated with other key metabolic pathways in vivo is poorly understood. Here, we describe an endogenous feedback circuit for regulation of p53 through its transcriptional target gene, Redd1, a stress-induced inhibitor of TOR complex 1 (TORC1) activity. Cells and tissues of Redd1(-/-) mice exhibit enhanced sensitivity to ionizing radiation and chemotherapy treatment, which we demonstrate is attributable to abnormally increased p53 protein level and activity in the absence of Redd1. We find that deregulation of p53 in this setting is not due to failed DNA repair or to increased p53 stabilization but, instead, to increased p53 translation. We show that Redd1 loss leads to elevated mammalian TORC1 (mTORC1) activity, which explains the increased p53 translation and protein levels. Together, these findings suggest that REDD1-mediated suppression of mTORC1 activity exerts feedback control on p53, thereby limiting the apoptotic response and contributing to cellular survival following DNA damage. This work therefore defines a role for REDD1 in the control of p53 in vivo, with potential therapeutic implications for cancer and for the variety of genetic diseases involving TOR pathway signaling components.
为了在 DNA 损伤后维持细胞内稳态，需要对 p53 的水平和活性进行精细控制。目前，人们对于这种调控如何与体内其他关键代谢途径相整合还知之甚少。在这里，我们描述了一种通过其转录靶基因 Redd1 对 p53 进行调节的内源性反馈回路，Redd1 是一种应激诱导的 TOR 复合物 1（TORC1）活性抑制剂。Redd1（-/-）小鼠的细胞和组织对电离辐射和化疗治疗表现出更高的敏感性，我们证明这归因于 Redd1 缺失时异常增加的 p53 蛋白水平和活性。我们发现，在这种情况下，p53 的失调不是由于 DNA 修复失败或 p53 稳定性增加引起的，而是由于 p53 翻译增加引起的。我们表明，Redd1 缺失会导致哺乳动物 TORC1（mTORC1）活性升高，这解释了 p53 翻译和蛋白水平的增加。总之，这些发现表明 REDD1 介导的 mTORC1 活性抑制对 p53 发挥反馈控制作用，从而限制细胞凋亡反应，并有助于 DNA 损伤后的细胞存活。因此，这项工作定义了 REDD1 在体内控制 p53 的作用，这对于癌症和涉及 TOR 途径信号成分的各种遗传疾病具有潜在的治疗意义。
