The Retinoblastoma Protein Selectively Represses E2F1 Targets via a TAAC DNA Element during Cellular Senescence
The Retinoblastoma Protein Selectively Represses E2F1 Targets via a TAAC DNA Element during Cellular Senescence
复制标题
视网膜母细胞瘤蛋白在细胞衰老过程中通过 TAAC DNA 元件选择性抑制 E2F1 靶标
DOI：
10.1074/jbc.m111.260679
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发表时间：
2012-10-26
影响因子：
4.8
通讯作者：
Tong, Tanjun
中科院分区：
文献类型：
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作者：
Chen, Tianda;Xue, Lixiang;Tong, Tanjun
视网膜母细胞瘤(Rb)蛋白在E2转录因子1(E2F1)靶基因的启动子(如增殖细胞核抗原和细胞周期蛋白A2(CcnA2))的启动子处介导异染色质的形成，并在细胞衰老过程中抑制这些基因。然而，RB招募的选择性仍然没有被很好地理解。在这里，我们证明了衰老相关基因是E2F1的直接靶标，并且在衰老细胞中也被异染色质抑制。相反，同样是E2F1靶的ARF和p27(KIP1)不受RB和异染色质形成的抑制。通过比较这些基因的启动子序列，我们发现了一个新的TAAC元件，它存在于细胞衰老抑制基因、增殖细胞核抗原和CcNA2启动子中，而不存在于ARF和p27KIP1启动子中。此TAAC元素与RB关联，是RB招聘所必需的。我们进一步确定，TAAC元件介导的RB结合需要E2F1结合位点，而不需要E2F1蛋白。这些结果为E2F1靶标的不同表达模式提供了新的分子机制，并为Rb介导的异染色质形成和细胞衰老过程中基因抑制的选择性提供了新的机制见解。
The retinoblastoma (Rb) protein mediates heterochromatin formation at the promoters of E2 transcription factor 1 (E2F1) target genes, such as proliferating cell nuclear antigen and cyclin A2 (CCNA2), and represses these genes during cellular senescence. However, the selectivity of Rb recruitment is still not well understood. Here, we demonstrate that a senescence-associated gene is a direct target of E2F1 and is also repressed by heterochromatin in senescent cells. In contrast, ARF and p27(KIP1), which are also E2F1 targets, are not repressed by Rb and heterochromatin formation. By comparing the promoter sequences of these genes, we found a novel TAAC element that is present in the cellular senescence-inhibited gene, proliferating cell nuclear antigen, and CCNA2 promoters but absent from the ARF and p27KIP1 promoters. This TAAC element associates with Rb and is required for Rb recruitment. We further determined that TAAC element-mediated Rb association requires the E2F1 binding site, but not E2F1 protein. These results provide a novel molecular mechanism for the different expression patterns of E2F1 targets and afford new mechanistic insight regarding the selectivity of Rb-mediated heterochromatin formation and gene repression during cellular senescence.