Gene expression profiling in cells with enhanced gamma-secretase activity.
Gene expression profiling in cells with enhanced gamma-secretase activity.
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DOI：
10.1371/journal.pone.0006952
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发表时间：
2009-09-18
期刊：
影响因子：
3.7
通讯作者：
Fraering PC
中科院分区：
文献类型：
--
作者：
Magold AI;Cacquevel M;Fraering PC
γ-分泌酶对许多 I 型膜蛋白底物的处理通过释放细胞内结构域 (ICD) 来触发信号级联，这些结构域在核转位后调节不同基因的转录，从而调节多种细胞和生物过程。由于 γ-分泌酶底物的数量正在快速增长，并且该酶是癌症和阿尔茨海默氏病的治疗靶点，因此绘制 γ-分泌酶活性易感基因转录图谱对于加深我们对特定受影响基因、分子功能和生物途径的认识非常重要。为了鉴定受γ-分泌酶活性转录影响的基因和分子功能，通过cDNA微阵列分析和比较了γ-分泌酶活性增强和抑制的中国仓鼠卵巢（CHO）细胞的细胞转录组。 FatiGO 对 1,981 个已识别基因进行的功能聚类揭示了具有多种活动和功能的群体的代表性过高和过低。通过实时 PCR 评估对 γ-分泌酶活性最显着的转录敏感性的单基因。在 21 个经过验证的基因中，PTPRG 和 AMN1 的转录显着减少以及 UPP1 的转录增加可能支持与癌症、干细胞和神经退行性疾病研究相关的细胞周期紊乱的数据。经验证的基因编码的蛋白质相互作用图谱完全依赖于基于证据的数据，并揭示了对 Wnt 通路成员（包括 WNT3A 和 DVL3）的广泛影响。有趣的是，TERA（一种功能未知的基因）的转录受到γ-分泌酶活性的影响，并且在分析的人类阿尔茨海默病脑皮质中显着改变。研究 γ-分泌酶活性对基因转录的影响揭示了几个受影响的分子功能簇，更具体地说，21 个基因对于更好地了解 γ-分泌酶的生物学及其在癌症和阿尔茨海默病病理学中的作用具有重要潜力。
Processing by γ-secretase of many type-I membrane protein substrates triggers signaling cascades by releasing intracellular domains (ICDs) that, following nuclear translocation, modulate the transcription of different genes regulating a diverse array of cellular and biological processes. Because the list of γ-secretase substrates is growing quickly and this enzyme is a cancer and Alzheimer's disease therapeutic target, the mapping of γ-secretase activity susceptible gene transcription is important for sharpening our view of specific affected genes, molecular functions and biological pathways. To identify genes and molecular functions transcriptionally affected by γ-secretase activity, the cellular transcriptomes of Chinese hamster ovary (CHO) cells with enhanced and inhibited γ-secretase activity were analyzed and compared by cDNA microarray. The functional clustering by FatiGO of the 1,981 identified genes revealed over- and under-represented groups with multiple activities and functions. Single genes with the most pronounced transcriptional susceptibility to γ-secretase activity were evaluated by real-time PCR. Among the 21 validated genes, the strikingly decreased transcription of PTPRG and AMN1 and increased transcription of UPP1 potentially support data on cell cycle disturbances relevant to cancer, stem cell and neurodegenerative diseases' research. The mapping of interactions of proteins encoded by the validated genes exclusively relied on evidence-based data and revealed broad effects on Wnt pathway members, including WNT3A and DVL3. Intriguingly, the transcription of TERA, a gene of unknown function, is affected by γ-secretase activity and was significantly altered in the analyzed human Alzheimer's disease brain cortices. Investigating the effects of γ-secretase activity on gene transcription has revealed several affected clusters of molecular functions and, more specifically, 21 genes that hold significant potential for a better understanding of the biology of γ-secretase and its roles in cancer and Alzheimer's disease pathology.
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