Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.
Fine-tuning p53 activity through C-terminal modification significantly contributes to HSC homeostasis and mouse radiosensitivity.
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DOI：
10.1101/gad.2024411
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发表时间：
2011-07
影响因子：
10.5
通讯作者：
Yunyuan V. Wang;Mathias Leblanc;N. Fox;J. Mao;Kelsey L. Tinkum;Kurt A. Krummel;Dannielle D. Engle
中科院分区：
文献类型：
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作者：
Yunyuan V. Wang;Mathias Leblanc;N. Fox;J. Mao;Kelsey L. Tinkum;Kurt A. Krummel;Dannielle D. Engle
造血干细胞（HSCs）的细胞周期调控在体内平衡过程中受到严格控制，并对外界应激做出反应。p53是一种众所周知的肿瘤抑制因子和多种应激信号的转导子，参与维持HSC的静止和自我更新。然而，控制其在HSC中的活性的机制，以及p53活性如何有助于HSC细胞周期控制，知之甚少。在这里，我们使用一个基因工程小鼠显示，p53 C-末端修饰是至关重要的控制HSC丰度在稳态和照射后的HSC和祖细胞增殖。由于HSC/祖细胞增殖的缺陷，防止p53 C-末端修饰使小鼠对辐射敏感，HSC/祖细胞增殖是辐射后恢复造血的关键决定因素。我们表明，微调的表达水平的细胞周期蛋白依赖性激酶抑制剂p21，p53的靶基因，有助于显着p53介导的造血系统的影响。这些结果对于理解干细胞移植中涉及的应激反应中的细胞竞争、从DNA损伤性癌症治疗的不良血液学效应中恢复以及放射防护策略的开发具有意义。
Cell cycle regulation in hematopoietic stem cells (HSCs) is tightly controlled during homeostasis and in response to extrinsic stress. p53, a well-known tumor suppressor and transducer of diverse stress signals, has been implicated in maintaining HSC quiescence and self-renewal. However, the mechanisms that control its activity in HSCs, and how p53 activity contributes to HSC cell cycle control, are poorly understood. Here, we use a genetically engineered mouse to show that p53 C-terminal modification is critical for controlling HSC abundance during homeostasis and HSC and progenitor proliferation after irradiation. Preventing p53 C-terminal modification renders mice exquisitely radiosensitive due to defects in HSC/progenitor proliferation, a critical determinant for restoring hematopoiesis after irradiation. We show that fine-tuning the expression levels of the cyclin-dependent kinase inhibitor p21, a p53 target gene, contributes significantly to p53-mediated effects on the hematopoietic system. These results have implications for understanding cell competition in response to stresses involved in stem cell transplantation, recovery from adverse hematologic effects of DNA-damaging cancer therapies, and development of radioprotection strategies.