The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation.
The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation.
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单纯疱疹病毒 2 型基因 ICP10PK 通过抑制 caspase-3 激活和 XIAP 上调来防止神经生长因子剥夺引起的细胞凋亡。
DOI：
10.1111/j.1471-4159.2007.04745.x
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发表时间：
2007
影响因子：
4.7
通讯作者：
Aurelian,Laure
中科院分区：
文献类型：
--
作者：
Wales,SamanthaQ;Li,Baiquan;Laing,JenniferM;Aurelian,Laure
单纯疱疹病毒2型（HSV-2）蛋白ICP 10 PK通过激活Ras/Raf-1/MEK/ERK通路在病毒感染的海马培养物中具有抗凋亡活性。为了排除其他病毒蛋白对细胞命运决定的可能贡献，我们检测了原代海马培养物和神经分化的PC 12细胞的存活率，这些细胞用ICP 10 PK转染，由神经生长因子（NGF）撤出引起的细胞凋亡。在模拟转染或用激酶阴性ICP 10突变体p139 TM转染的培养物中，NGF剥夺引起细胞凋亡，但在ICP 10 PK转染的培养物中不引起细胞凋亡。在一个克隆（PC 47）中，ICP 10 PK通过上调/稳定腺苷酸环化酶（AC）、激活PKA和MEK以及两种途径对细胞外信号调节激酶激活的会聚来抑制caspase-3激活。抗凋亡蛋白Bag-1和Bcl-2被稳定化，促凋亡蛋白Bad被磷酸化（失活）。在另一个克隆（PC 70）中，ICP 10 PK通过MEK依赖性上调抗凋亡蛋白XIAP（抑制加工的caspase-3的活性）和下调促凋亡蛋白Smac/DIABLO抑制凋亡。这可能是细胞类型特异性的，但杆状病毒p35蛋白在PC 12细胞中没有增强ICP 10 PK的神经保护活性，表明ICP 10 PK抑制半胱天冬酶活化和活性。这些数据表明，ICP 10 PK抑制细胞凋亡独立于其他病毒蛋白，是一个有前途的神经元基因治疗平台。
The herpes simplex virus type 2 (HSV‐2) protein ICP10PK has anti‐apoptotic activity in virus‐infected hippocampal cultures through activation of the Ras/Raf‐1/MEK/ERK pathway. To exclude the possible contribution of other viral proteins to cell fate determination, we examined the survival of primary hippocampal cultures and neuronally differentiated PC12 cells transfected with ICP10PK from apoptosis caused by nerve growth factor (NGF) withdrawal. NGF deprivation caused apoptosis in cultures mock‐transfected or transfected with the kinase‐negative ICP10 mutant p139TM, but not in ICP10PK‐transfected cultures. In one clone (PC47), ICP10PK inhibited caspase‐3 activation through up‐regulation/stabilization of adenylate cyclase (AC), activation of PKA and MEK, and the convergence of the two pathways on extracellular signal‐regulated kinase activation. The anti‐apoptotic proteins Bag‐1 and Bcl‐2 were stabilized and the pro‐apoptotic protein Bad was phosphorylated (inactivated). In another clone (PC70), ICP10PK inhibited apoptosis through MEK‐dependent up‐regulation of the anti‐apoptotic protein XIAP (that inhibits the activity of processed caspase‐3) and down‐regulation of the apoptogenic protein Smac/DIABLO. This may be cell‐type specific, but the baculovirus p35 protein did not potentiate the neuroprotective activity of ICP10PK in PC12 cells, suggesting that ICP10PK inhibits both caspase activation and activity. The data indicate that ICP10PK inhibits apoptosis independent of other viral proteins and is a promising neuronal gene therapy platform.