Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation
Nitric oxide negatively regulates proliferation and promotes neuronal differentiation through N-Myc downregulation
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DOI：
10.1242/jcs.01348
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发表时间：
2004-09-15
影响因子：
4
通讯作者：
Contestabile, A
中科院分区：
文献类型：
--
作者：
Ciani, E;Severi, S;Contestabile, A
一氧化氮（NO）已被发现作为一个重要的细胞增殖的负调节剂在几个系统。我们在这里报告，NO负调控神经元细胞前体细胞的增殖，并通过下调癌基因N-Myc促进其分化。我们已经研究了这种调节功能的NO在神经母细胞瘤细胞系（SK-N-BE）和在原代小脑颗粒细胞培养。在神经元型一氧化氮合酶（nNOS）过度表达神经母细胞瘤细胞系暴露于视黄酸的分化作用，NO减缓增殖和加速分化向神经元型。这种作用伴随着N-Myc表达的平行减少。类似的结果可以在父母SK-N-BE细胞通过提供一个外源性来源的NO。药理学控制表明，NO的细胞增殖和N-Myc表达的调节作用介导的cGMP作为中间信使。此外，NO被发现调节NMyc基因启动子的转录活性的E2 F调控区，可能通过控制Rb磷酸化状态，我们发现是负调控NO。在小脑颗粒细胞培养，NOS抑制增加分裂率的神经元前体细胞，在平行增强N-Myc的表达。由于高N-Myc表达水平对于神经母细胞瘤进展以及神经元前体的增殖是必不可少的，因此NO对其的负调节突出了这种重要信使分子的新的生理病理学功能。
Nitric oxide (NO) has been found to act as an important negative regulator of cell proliferation in several systems. We report here that NO negatively regulates proliferation of neuronal cell precursors and promotes their differentiation by downregulating the oncogene N-Myc. We have studied this regulatory function of NO in neuroblastoma cell lines (SK-N-BE) and in primary cerebellar granule cell cultures. In a neuronal NO synthase (nNOS) overexpressing neuroblastoma cell line exposed to the differentiative action of retinoic acid, NO slowed down proliferation and accelerated differentiation towards a neuronal phenotype. This effect was accompanied by a parallel decrease of N-Myc expression. Similar results could be obtained in parental SK-N-BE cells by providing an exogenous source of NO. Pharmacological controls demonstrated that NO's regulatory actions on cell proliferation and N-Myc expression were mediated by cGMP as an intermediate messenger. Furthermore, NO was found to modulate the transcriptional activity of NMyc gene promoter by acting on the E2F regulatory region, possibly through the control of Rb phosphorylation state, that we found to be negatively regulated by NO. In cerebellar granule cell cultures, NOS inhibition increased the division rate of neuronal precursors, in parallel with augmented N-Myc expression. Because a high N-Myc expression level is essential for neuroblastoma progression as well as for proliferation of neuronal precursors, its negative regulation by NO highlights a novel physiopathological function of this important messenger molecule.