A novel role for serum response factor in neuronal survival
A novel role for serum response factor in neuronal survival
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DOI：
10.1523/jneurosci.4868-03.2004
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发表时间：
2004-03-03
影响因子：
5.3
通讯作者：
Xia, ZG
中科院分区：
文献类型：
--
作者：
Chang, SH;Poser, S;Xia, ZG
最近的研究表明，脑源性神经营养因子（BDNF）的神经保护作用是由细胞外信号调节激酶（ERK）和磷脂酰肌醇-3激酶（PI 3 K）介导的。然而，ERK和PI 3 K发挥神经保护作用的机制尚未完全了解。由于ERK 1/2和PI 3 K都刺激血清反应元件（SRE）介导的基因表达，而血清反应因子（SRF）对于SRE介导的转录是必不可少的，因此我们研究了SRF是否有助于ERK 1/2和PI 3 K的神经保护。为了实现这一目标，我们使用了一个既定的实验范式，其中BDNF保护出生后的皮质神经元对营养剥夺和喜树碱诱导的DNA损伤。BDNF对喜树碱的保护主要由ERK 1/2活化介导，而其对营养剥夺的保护主要通过刺激PI 3 K途径（Hetman et al.，1999年）。在这里，我们证明了野生型SRF的表达足以保护出生后的皮质神经元免受喜树碱或营养剥夺。显性负性SRF的表达部分逆转了BDNF对两种凋亡损伤的神经保护作用。此外，显性负SRF抑制神经保护对营养戒断提供了一个组成性的活性PI 3 K的表达。此外，通过表达组成型活性丝裂原活化蛋白激酶激酶1（一种激活ERK 1/2的上游激酶）对喜树碱的保护作用也被显性负性SRF的表达阻断。这些数据表明，SRF对于脑源性神经营养因子保护皮质神经元免受营养剥夺和DNA损伤来说是必要且充分的。我们的数据提供了SRF在神经元中的生物学功能和ERK 1/2和PI 3 K通路共同的新型下游神经保护机制的直接证明。
Recent studies indicate that neuroprotection afforded by brain-derived neurotrophic factor ( BDNF) is mediated by extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K). However, the mechanisms by which ERK and PI3K exert neuroprotection are not completely understood. Because ERK1/2 and PI3K both stimulate serum response element (SRE)-mediated gene expression, and serum response factor (SRF) is indispensable for SRE-mediated transcription, we investigated whether SRF contributes to ERK1/2 and PI3K neuroprotection. To accomplish this goal, we used an established experimental paradigm in which BDNF protects postnatal cortical neurons against both trophic deprivation and camptothecin-induced DNA damage. BDNF protection against camptothecin is mediated primarily by ERK1/2 activation, whereas its protection against trophic deprivation is mainly through stimulation of the PI3K pathway (Hetman et al., 1999). Here we demonstrate that expression of a wild-type SRF is sufficient to protect postnatal cortical neurons against camptothecin or trophic deprivation. Expression of a dominant-negative SRF partially reversed BDNF neuroprotection against both apoptotic insults. Moreover, the dominant-negative SRF inhibited neuroprotection against trophic withdrawal afforded by expression of a constitutive active PI3K. In addition, protection against camptothecin by expression of constitutive active mitogen-activated protein kinase kinase 1, an upstream kinase that activates ERK1/2, was also blocked by expression of the dominant-negative SRF. These data suggest that SRF is both necessary and sufficient for BDNF neuroprotection of cortical neurons against trophic deprivation and DNA damage. Our data provide a direct demonstration of a biological function of SRF in neurons and a novel downstream neuroprotective mechanism common to both ERK1/2 and PI3K pathways.