Li L, Hung A C, Porter A G
Cell Death and Human Disease Group, Division of Cancer and Developmental Cell Biology, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Republic of Singapore.
Cell Death Differ. 2008 May;15(5):879-88. doi: 10.1038/cdd.2008.8. Epub 2008 Feb 1.
Identification of AP-1 target genes in apoptosis and differentiation has proved elusive. Secretogranin II (SgII) is a protein widely distributed in nervous and endocrine tissues, and abundant in neuroendocrine granules. We addressed whether SgII is regulated by AP-1, and if SgII is involved in neuronal differentiation or the cellular response to nitrosative stress. Nitric oxide (NO) upregulated sgII mRNA dependent on a cyclic AMP response element (CRE) in the sgII promoter, and NO stimulated SgII protein secretion in neuroblastoma cells. Upregulation of sgII mRNA, sgII CRE-driven gene expression and SgII protein synthesis/export were attenuated in cells transformed with dominant-negative c-Jun (TAM67), which became sensitized to NO-induced apoptosis and failed to undergo nerve growth factor-dependent neuronal differentiation. Stable transformation of TAM67 cells with sgII restored neuronal differentiation and resistance to NO. RNAi knockdown of sgII in cells expressing functional c-Jun abolished neuronal differentiation and rendered the cells sensitive to NO-induced apoptosis. Therefore, SgII represents a key AP-1-regulated protein that counteracts NO toxicity and mediates neuronal differentiation of neuroblastoma cells.
在细胞凋亡和分化过程中鉴定AP - 1靶基因一直颇具难度。分泌粒蛋白II（SgII）是一种广泛分布于神经和内分泌组织的蛋白质，在神经内分泌颗粒中含量丰富。我们研究了SgII是否受AP - 1调控，以及SgII是否参与神经元分化或细胞对亚硝化应激的反应。一氧化氮（NO）通过sgII启动子中的环磷酸腺苷反应元件（CRE）上调sgII mRNA，并且NO刺激神经母细胞瘤细胞中SgII蛋白的分泌。在用显性负性c - Jun（TAM67）转化的细胞中，sgII mRNA、sgII CRE驱动的基因表达以及SgII蛋白合成/分泌的上调均受到抑制，这些细胞对NO诱导的凋亡变得敏感，并且无法进行神经生长因子依赖性的神经元分化。用sgII对TAM67细胞进行稳定转化可恢复神经元分化并增强对NO的抗性。在表达功能性c - Jun的细胞中，通过RNA干扰敲低sgII可消除神经元分化，并使细胞对NO诱导的凋亡敏感。因此，SgII是一种关键的受AP - 1调控的蛋白质，可对抗NO毒性并介导神经母细胞瘤细胞的神经元分化。
