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首页> 外文期刊>Cell cycle >Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.
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Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

机译：分化和损伤修复信号调节角质形成细胞中E2F和pRB蛋白与新型靶基因的相互作用。

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E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.
机译：E2F转录因子是损伤后表皮形态发生和再生的关键。 E2F目标基因参与表皮形成和修复的确切性质尚未确定。这些基因的鉴定对于了解E2F蛋白如何调节表皮稳态和转化的基本方面至关重要。我们已经进行了全基因组筛选，使用CpG岛微阵列分析来鉴定人角质形成细胞中E2F3和E2F5结合的新型启动子。我们进一步表征了这些基因中的几个，并确定了多个E2F和成视网膜细胞瘤（pRb）家族蛋白与它们在指数增殖的细胞中缔合。我们还评估了对E2F和pRb结合这些基因的影响，以响应由骨形态发生蛋白6（BMP-6）诱导的分化，或对转化生长因子-β（TGF-β）诱导的修复机制的激活。这些研究表明E2F和/或pRb家族蛋白的结合谱中启动子和细胞因子的特异性变化。例如，在BMP-6处理的细胞中，E2F1、3、4和p107被募集到N-myc启动子，而在存在TGF-beta的情况下，E2F1、3、4、5，p107和p130结合到该启动子。在功能上，这些不同的相互作用通过涉及E2F与启动子结合并与pRb家族蛋白结合的机制，导致N-myc基因的BMP-6和TGF-β受到转录抑制。因此，E2F和pRb家族蛋白的多种组合可以响应表皮角质形成细胞的分化和损伤修复刺激而与给定的靶标启动子缔合并转录调控。

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