Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons
Suppressor of cytokine signaling-3 suppresses the ability of activated signal transducer and activator of transcription-3 to stimulate neurite growth in rat primary sensory neurons
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DOI：
10.1523/jneurosci.2160-06.2006
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发表时间：
2006-09-13
影响因子：
5.3
通讯作者：
Richardson, Peter M.
中科院分区：
文献类型：
--
作者：
Miao, Tizong;Wu, Dongsheng;Richardson, Peter M.
神经生成细胞因子的作用由gp 130受体介导，gp 130受体激活包括转录因子STAT 3（信号转导子和转录激活子）在内的几种信号分子，而转录因子STAT 3又受到SOCS 3（细胞因子信号传导抑制子）的反馈抑制。gp 130受体的激活与轴突生长有关，特别是在再生过程中，但STAT 3的具体贡献是相互矛盾的报道的主题。大鼠背根神经节中SOCS 3 mRNA的测量表明，在周围神经损伤后，这种抑制性分子有明显的诱导作用。通过慢病毒转导产生条件激活的STAT 3、天然SOCS 3或具有显性负作用的突变体SOCS 3，在体外研究了STAT 3和SOCS 3在成年大鼠初级感觉神经元中的功能。SOCS 3构建体有效抑制成神经细胞瘤细胞系中STAT 3的酪氨酸磷酸化，并阻断内源性STAT 3或条件活化的STAT 3嵌合体在初级感觉神经元中的核积累。在这样的神经元中，至少在基础条件下，STAT 3的转导和激活增强了神经突生长，用SOCS 3转导减少了神经突生长，并且用突变体SOCS 3转导增强了神经突生长。总之，STAT 3信号通过激活未鉴定基因的转录而有利于轴突生长，而SOCS 3通过抑制STAT 3和/或其他转录因子而不利于轴突生长。
The actions of the neuropoietic cytokines are mediated by the gp130 receptor, which activates several signaling molecules including the transcription factor STAT3 (signal transducer and activator of transcription), which, in turn, is subject to feedback inhibition by SOCS3 (suppressor of cytokine signaling). Activation of the gp130 receptor has been implicated in axonal growth particularly during regeneration, but the specific contribution of STAT3 is the subject of conflicting reports. Measurements of SOCS3 mRNA in rat dorsal root ganglia showed a significant induction in this inhibitory molecule after peripheral nerve injury. The functions of STAT3 and SOCS3 in adult rat primary sensory neurons were investigated in vitro through transduction of lentiviruses yielding a conditionally activated STAT3, native SOCS3, or a mutant SOCS3 with dominant-negative actions. The SOCS3 construct was effective in inhibiting tyrosine phosphorylation of STAT3 in a neuroblastoma cell line and in blocking nuclear accumulation of endogenous STAT3 or of the conditionally activated STAT3 chimera in primary sensory neurons. In such neurons, transduction and activation of STAT3 enhanced neurite growth, transduction with SOCS3 reduced neurite outgrowth, and transduction with mutant SOCS3 enhanced neurite growth, at least under basal conditions. In conclusion, STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes, and SOCS3 is detrimental to axonal growth through inhibition of STAT3 and/or other transcription factors.