Differential Proteomics Analysis Reveals a Role for E2F2 in the Regulation of the Ahr Pathway in T Lymphocytes
Differential Proteomics Analysis Reveals a Role for E2F2 in the Regulation of the Ahr Pathway in T Lymphocytes
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DOI：
10.1074/mcp.m110.001263
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发表时间：
2010-10-01
影响因子：
7
通讯作者：
Zubiaga, Ana M.
中科院分区：
文献类型：
--
作者：
Azkargorta, Mikel;Fullaondo, Asier;Zubiaga, Ana M.
E2F 转录因子 (E2F1-8) 以其在细胞增殖中的作用而闻名，尽管很明显它们通过不同靶基因的转录调节来调节许多其他生物过程。然而，每个 E2F 调控的特定基因组仍有待表征。为了深入了解 E2F2 调节的分子途径，我们分析了缺乏 E2F2 的抗原受体激活 T 细胞的蛋白质组。我们报告 E2F2 的缺失会导致芳基烃受体途径失调。相对于野生型 (WT)(1) 对照，增殖的 E2F2(-/-) T 淋巴细胞表达显着更高水平的 Aip、Ahr 和 Arnt。 Aip 水平增加的机制似乎很简单，涉及 E2F2 对 Aip 基因启动子的直接调节。尽管 Ahr 和 Arnt 启动子也结合 E2F2，但它们的调控似乎更加复杂。然而，与WT对照相比，暴露于环境外源物2,3,7,8-四氯二苯并-对二恶英（TCDD）（Ahr途径的一种众所周知的外源配体）会导致Ahr靶基因Cyp1a1的过度表达，并导致E2F2（-/-）T细胞对TCDD触发的细胞凋亡的敏感性增加。这些结果表明 E2F2 通过 Ahr 途径的负调节来调节细胞对外源信号的敏感性。分子与细胞蛋白质组学 9：2184 -2194，2010。
E2F transcription factors (E2F1-8) are best known for their role in cell proliferation, although it is clear that they regulate many other biological processes through the transcriptional modulation of distinct target genes. However, the specific set of genes regulated by each E2F remains to be characterized. To gain insight into the molecular pathways regulated by E2F2, we have analyzed the proteome of antigen receptor-activated T cells lacking E2F2. We report that loss of E2F2 results in a deregulated Aryl-hydrocarbon-receptor pathway. Proliferating E2F2(-/-) T lymphocytes expressed significantly higher levels of Aip, Ahr, and Arnt relative to wild-type (WT)(1) controls. The mechanism for increased levels of Aip appears straightforward, involving direct regulation of the Aip gene promoter by E2F2. Although the Ahr and Arnt promoters also bind E2F2, their regulation appears to be more complex. Nevertheless, exposure to the environmental xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known exogenous ligand of the Ahr pathway, led to overexpression of the Ahr target gene Cyp1a1, and to increased sensitivity to TCDD-triggered apoptosis in E2F2(-/-) T cells compared with WT controls. These results suggest that E2F2 modulates cellular sensitivity to xenobiotic signals through the negative regulation of the Ahr pathway. Molecular & Cellular Proteomics 9:2184 -2194, 2010.