NRAGE Mediates p38 Activation and Neural Progenitor Apoptosis via the Bone Morphogenetic Protein Signaling Cascade
NRAGE Mediates p38 Activation and Neural Progenitor Apoptosis via the Bone Morphogenetic Protein Signaling Cascade
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DOI：
10.1128/mcb.26.9.3681.2006
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发表时间：
2006-05
影响因子：
5.3
通讯作者：
S. Kendall;Chiara Battelli;Sarah Irwin;Jane Mitchell;George N. Nikopolous;Stephen Bellum;Daniel P. Moore-Da
中科院分区：
文献类型：
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作者：
S. Kendall;Chiara Battelli;Sarah Irwin;Jane Mitchell;George N. Nikopolous;Stephen Bellum;Daniel P. Moore-Da
了解控制神经祖细胞谱系承诺、有丝分裂停止和分化为功能后代的分子事件与我们对新皮层发育的理解密切相关。骨形态发生蛋白（BMPs）家族成员通过Smad和TAK1激活的联合作用在神经发生过程中调节神经分化和凋亡中发挥关键作用。我们证明BMP信号是诱导神经祖细胞凋亡所必需的，而NRAGE是信号级联的必要组成部分。NRAGE具有与TAK1-TAB1-XIAP复合体结合并发挥作用的能力，促进p38的激活。破坏NRAGE或任何其他非典型信号级联的成员足以阻断p38的激活，从而阻断BMP暴露产生的促凋亡信号。NRAGE的功能独立于Smad信号，但引入显性阴性的Smad5也可以挽救神经祖细胞凋亡，这表明规范和非规范途径可以汇聚并调节bmp介导的细胞凋亡。总的来说，这些结果确定了NRAGE是BMP信号传导的一个组成部分，并阐明了它在收集和使用标准Western blotting技术时的作用。正如预期的那样，NRAGE过表达导致p53水平升高。p53增加的直接后果是长期暴露于NRAGE后p21 waf1和p27 kip1的积累。CDK抑制剂的增加反映在活性p-pRb水平的升高上。此外，为了支持NRAGE作为p38的激活剂，过表达显著增加了p38在前48 h复合体内的活性形式，从而激活p38。活跃的p38促进细胞周期的进展，而Smad信号则促进生长停滞。这种提前重新进入S期导致p53的激活，促进凋亡细胞的激活和形成，导致caspase激活。然而，为了允许神经分化，NRAGE信号需要一个基础水平来介导细胞周期最终退出的生长停滞。
Understanding the molecular events that govern neural progenitor lineage commitment, mitotic arrest, and differentiation into functional progeny are germane to our understanding of neocortical development. Members of the family of bone morphogenetic proteins (BMPs) play pivotal roles in regulating neural differentiation and apoptosis during neurogenesis through combined actions involving Smad and TAK1 activation. We demonstrate that BMP signaling is required for the induction of apoptosis of neural progenitors and that NRAGE is a mandatory component of the signaling cascade. NRAGE possesses the ability to bind and function with the TAK1-TAB1-XIAP complex facilitating the activation of p38. Disruption of NRAGE or any other member of the noncanonical signaling cascaded is sufficient to block p38 activation and thus the proapoptotic signals generated through BMP exposure. The function of NRAGE is independent of Smad signaling, but the intro- duction of a dominant-negative Smad5 also rescues neural progenitor apoptosis, suggesting that both canonical and noncanonical pathways can converge and regulate BMP-mediated apoptosis. Collectively, these results establish NRAGE as an integral component in BMP signaling and clarify its role during were collected and subjected to standard Western blotting techniques. As anticipated, NRAGE overexpression resulted in increased p53 levels. A direct consequence of increased p53 was the accumulation of p21 waf1 and p27 kip1 after prolonged exposure to NRAGE. This increase in CDK inhibitors was reflected in elevated levels of active p-pRb. Furthermore, in support of NRAGE as an activator of p38, overexpression significantly increased the active form of p38 within the first 48 h. complex to activate p38. Active p38 promotes progression through the cell cycle, while Smad signaling facilitates growth arrest. This precocious reentry into S phase leads to the activation of p53 that facilitates activation and formation of the apoptosome, resulting in caspase activation. However, a basal level of NRAGE signaling is required to mediate growth arrest for terminal exit from the cell cycle in order to permit neural differentiation.