Phospholipase Cb1 regulates proliferation of neuronal cells
Phospholipase Cb1 regulates proliferation of neuronal cells
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磷脂酶 Cb1 调节神经元细胞增殖
DOI：
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Suzanne Scarlata
中科院分区：
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作者：
Osama Garwain;K. Valla;Suzanne Scarlata
细胞已经发展出谱系特异性机制来控制增殖并在分化时驱动形态学变化。分化的一个标志是信号分子的组装，这些信号分子抑制细胞外信号，例如G蛋白调节的酶磷脂酶Cb（PLCb）的产生，它从感觉刺激中产生钙信号。我们发现在大多数癌细胞系中，PLCb 1水平与细胞增殖呈正相关。然而，在神经元谱系的细胞中，降低PLCb 1水平增加增殖速率。使用生物化学和生物物理学方法的组合，我们发现，在G1期，PLCb 1的胞质群体与细胞周期蛋白依赖性激酶16（CDK 16）相关联，CDK 16是一种神经元特异性酶，由细胞周期蛋白Y激活以抑制抗癌蛋白p27 Kip 1。PLCb 1的结合直接抑制CDK 16活性，进而降低细胞进入S期的能力。卡巴胆碱激活Gaq导致PLCb从胞质溶胶移动到质膜，减少其与CDK 16的结合。类似地，激活的Gaq的过表达将PLCb 1移动到膜上，逆转G1停滞，并促进增殖，从而将外部刺激与细胞增殖联系起来。我们的研究结果提出了一种模型，其中发生在分化开始时的PLCb 1的瞬时高表达通过与CDK 16的结合将细胞阻滞在G1期，并允许CDK 16过渡到其有丝分裂后的神经突生长和突触囊泡运输功能。PLCb 1在神经元细胞增殖中的新作用提供了一种独特的相互作用，可以操纵这种相互作用来引导细胞进入神经元表型或开发神经母细胞瘤的疗法。加尔维斯顿岛，瓦拉，K.，Scarlata，S.磷脂酶Cb 1调节神经细胞增殖。FASEB J. 32，2891-2898（2018）。www.fasebj.org
Cells have developed lineage‐specific mechanisms to control proliferation and drive morphologic changes upon differentiation. A hallmark of differentiation is the assembly of signaling molecules that transduce extracellular signals, such as the production of the G protein‐regulated enzyme phospholipase Cb (PLCb), which generates calcium signals from sensory stimuli. We found that in most cancerous cell lines there is positive correlation between PLCb 1 levels and cell proliferation. In cells of neuronal lineage, however, reducing PLCb 1 levels increases the rate of proliferation. Using a combination of biochemical and biophysical methods, we find that, in the G1 phase, a cytosolic population of PLCb 1 associates with cyclin‐dependent kinase 16 (CDK16), a neuron‐specific enzyme that is activated by cyclin Y to inactivate the antioncogenic protein p27Kip1. Binding of PLCb1 directly inhibits CDK16 activity and in turn reduces the ability of cells to enter the S phase. Activation of Gaq by carbachol causes movement of PLCb from the cytosol to the plasma membrane, reducing its association with CDK16. Similarly, the overexpression of activated Gaq moves PLCb 1 to the membrane, reverses G1 arrest, and promotes proliferation, thereby connecting external stimuli with cell proliferation. Our results present a model in which the transient high expression of PLCb1 that occurs at the onset of differentiation arrests cells in the G1 phase through its association with CDK16 and allows CDK16 to transition to its postmitotic function of neurite outgrowth and trafficking of synaptic vesicles. The novel role of PLCb 1 in neuronal cell proliferation offers a unique interaction that can be manipulated to guide cells into a neuronal phenotype or to develop therapies for neuroblastomas.— Garwain, O., Valla, K., Scarlata, S. Phospholipase Cb 1 regulates proliferation of neuronal cells. FASEB J. 32, 2891–2898 (2018). www.fasebj.org
影响因子：
8
作者：
T. Okuda;J. Cleveland;J. Downing
通讯作者：
T. Okuda;J. Cleveland;J. Downing