文章：

RB肿瘤抑制通路在造血系统氧化应激反应中的作用

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system

原文发布日期：2008-09-18

DOI: 10.1038/nrc2504

类型: Review Article

开放获取: 否

要点：

1. Reactive oxygen species (ROS) produced at the mitochondrial respiratory chain and to a lesser extent by peroxisomes and plasma membrane-bound NADPH oxidases have a crucial role in signalling pathways in the cell, including a requirement for ROS to promote S phase entry.
2. Excess ROS can lead to cell cycle arrest, senescence or cell death and thus proper management of ROS is required to prevent premature ageing and disease.
3. Increased ROS levels in the haematopoietic system lead to stem cell depletion and bone marrow failure and are associated with activation of the retinoblastoma (RB) pathway through induction of the cyclin-dependent kinase inhibitor INK4A.
4. RB is required to maintain the haematopoietic stem cell (HSC) pool and prevent aberrant S phase entry of HSCs in response to proliferative stress.
5. Defects in Rb1-deficient haematopoiesis are due in part to non-cell-autonomous events, including the influence of the bone marrow niche on the development of myeloproliferative disease and the sensitivity of stem cells and erythroid cells to proliferative stress. These observations are indicative of a role for RB in regulating the stromal microenvironment.
6. Disruption of ataxia telangiectasia mutated (ATM) or the Forkhead box O (Foxo) transcription factors in mice leads to increased ROS levels in HSCs that induce p38 mitogen-activated protein kinase activity, INK4A expression, downregulation of N-cadherin and increased stem cell recruitment into the cell cycle, probably due to reduced expression of the cyclin-dependent kinase inhibitors p21 and p27. Thus, ATM and Foxo act upstream of RB in the response of the cell to ROS.
7. Proliferative stress also induces erythroid maturation defects in the Rb1-null mouse that include failure to exit the cell cycle during terminal differentiation, increased ROS levels, increased DNA damage and altered management of mitochondrial mass.
8. Acetylation of RB modulates its rate of turnover in response to oxidative stress and protein phosphatase 2A-dependent dephosphorylation modulates its activity.
9. The role of the RB pathway in responding to oxidative stress in the haematopoietic system has implications for how other cell types respond to ROS, including human tumours that lack a functional RB pathway. Such cancers exhibit defective stress responses and increased levels of ROS, making them more susceptible to chemotherapy-induced death.

要点翻译：

1. 线粒体呼吸链产生的活性氧（ROS），以及过氧化物酶体和质膜结合的NADPH氧化酶在较小程度上产生的ROS，在细胞信号通路中具有关键作用，包括ROS促进S期进入的需求。
2. 过量的ROS会导致细胞周期停滞、衰老或细胞死亡，因此需要适当管理ROS以防止过早衰老和疾病。
3. 造血系统中ROS水平升高会导致干细胞耗竭和骨髓衰竭，并通过诱导细胞周期蛋白依赖性激酶抑制剂INK4A与视网膜母细胞瘤（RB）通路的激活相关。
4. RB是维持造血干细胞（HSC）池并在增殖应激下防止HSC异常进入S期所必需的。
5. Rb1缺陷造血功能的缺陷部分归因于非细胞自主性事件，包括骨髓微环境对骨髓增生性疾病发展的影响以及干细胞和红系细胞对增殖应激的敏感性。这些观察结果表明RB在调节基质微环境中发挥作用。
6. 小鼠中共济失调毛细血管扩张突变（ATM）或Forkhead box O（Foxo）转录因子的破坏会导致HSC中ROS水平升高，从而诱导p38丝裂原活化蛋白激酶活性、INK4A表达、N-钙粘蛋白下调，并增加干细胞进入细胞周期的招募，这可能是由于细胞周期蛋白依赖性激酶抑制剂p21和p27的表达减少。因此，在细胞对ROS的反应中，ATM和Foxo作用于RB的上游。
7. 增殖应激还会诱导Rb1缺失小鼠出现红系成熟缺陷，包括在终末分化期间未能退出细胞周期、ROS水平升高、DNA损伤增加以及线粒体质量管理的改变。
8. RB的乙酰化调节其在氧化应激下的周转率，而蛋白磷酸酶2A依赖性去磷酸化调节其活性。
9. RB通路在造血系统响应氧化应激中的作用对其他细胞类型（包括缺乏功能性RB通路的人类肿瘤）如何响应ROS具有启示意义。此类癌症表现出应激反应缺陷和ROS水平升高，使其更容易受到化疗诱导的死亡。

英文摘要：

Exposure to pro-oxidants and defects in the repair of oxidative base damage are associated with disease and ageing and also contribute to the development of anaemia, bone marrow failure and haematopoietic malignancies. This Review assesses emerging data indicative of a specific role for the RB tumour suppressor pathway in the response of the haematopoietic system to oxidative stress. This is mediated through signalling pathways that involve DNA damage sensors, forkhead box O (Foxo) transcription factors and p38 mitogen-activated protein kinases and has downstream consequences for cell cycle progression, antioxidant capacity, mitochondrial mass and cellular metabolism.

摘要翻译： 

促氧化剂暴露及氧化性碱基损伤修复缺陷与疾病和衰老相关，并促成贫血、骨髓衰竭及造血恶性肿瘤的发生。本综述评估了新兴数据，这些数据表明RB肿瘤抑制通路在造血系统应对氧化应激中具有特定作用；该作用通过涉及DNA损伤感受器、Foxo转录因子及p38丝裂原活化蛋白激酶的信号通路介导，并对细胞周期进程、抗氧化能力、线粒体质量及细胞代谢产生下游影响。

原文链接：

The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system