Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway
Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway
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DOI：
10.1080/13550280290167885
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发表时间：
2002-12-01
影响因子：
3.2
通讯作者：
Amini, S
中科院分区：
文献类型：
--
作者：
Peruzzi, F;Gordon, J;Amini, S
HIV-1在感染的早期阶段进入大脑，主要存在于数量有限的巨噬细胞/小胶质细胞和星形胶质细胞中。然而，这些细胞的感染可能无法解释艾滋病相关痴呆症中出现的大量神经元病理学，这表明HIV-1感染细胞释放的因子在引发导致神经变性的级联反应中发挥作用。我们的研究结果表明，达特，HIV-1的有效的调节蛋白，它是由感染的细胞分泌，并可以通过跨细胞的方式影响邻近的未感染的细胞，可以影响多种生物学事件，导致神经元损伤。这些发现表明，用达特处理神经元细胞影响MAPK/ERK 1/2活性，MAPK/ERK 1/2活性是神经生长因子（NGF）信号通路的下游中枢成分。此外，我们的数据表明，用达特处理细胞严重降低了p35的表达，p35是cdk 5的神经元特异性激活剂，cdk 5是一种细胞周期蛋白依赖性激酶，其磷酸化包括神经丝在内的几种神经元蛋白，并在神经元分化和存活中起重要作用。平行地，达特可以结合细胞蛋白Puralpha，其与cdk 5缔合。此外，来自Pura敲除动物的结果揭示了p35活性的降低，指出Puralpha与cdk 5的关联在cdk 5：p35复合物的活性中的重要性。这些数据证明了HIV-1达特和Pura在神经元细胞中的NGF信号转导通路的失调中的协同性。
HIV-1 enters the brain at the early stage of infection and resides primarily in a limited number of macrophages/microglia and astrocytes. Infection of these cells, however, may not explain the massive neuronal pathology which is seen in AIDS-associated dementia, suggesting a role for factors released from HIV-1 infected cells that trigger a cascade of events leading to neurodegeneration. Our results indicate that Tat, the potent regulatory protein of HIV-1 which is secreted by infected cells and can affect neighboring uninfected cells by transcellular means, can influence multiple biological events that lead to neuronal injury. These findings demonstrate that treatment of neuronal cells with Tat affects MAPK/ERK1/2 activity, the downstream central component of the nerve growth factor (NGF) signaling pathway. Furthermore, our data indicate that treatment of cells with Tat severely decreases expression of p35, a neuron-specific activator of cdk5, a cyclin dependent kinase that phosphorylates several neuronal proteins including neurofilament, and plays an important role in neuronal differentiation and survival. In parallel, Tat can bind to the cellular protein, Puralpha, which associates with cdk5. Further, results from Pura knockout animals revealed a decrease in p35 activity, pointing to the importance of Puralpha association with cdk5 in the activity of cdk5:p35 complex. These data demonstrate the cooperativity between HIV-1 Tat and the Pura in deregulation of the NGF signal transduction pathway in neuronal cells.