RETINOBLASTOMA PROTEIN SWITCHES THE E2F SITE FROM POSITIVE TO NEGATIVE ELEMENT
RETINOBLASTOMA PROTEIN SWITCHES THE E2F SITE FROM POSITIVE TO NEGATIVE ELEMENT
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DOI：
10.1038/358259a0
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发表时间：
1992-07-16
期刊：
影响因子：
64.8
通讯作者：
DEAN, DC
中科院分区：
文献类型：
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作者：
WEINTRAUB, SJ;PRATER, CA;DEAN, DC
最初，E2F 位点被确定为腺病毒早期基因启动子中的元件，这些元件是早期蛋白 E1a 激活这些基因所必需的（参考文献 1）。 E2F 启动子元件已被证明对于几个基因的转录激活非常重要，这些基因对于细胞周期的进展至关重要2-4。在细胞周期的 G1 期，E2F 蛋白与细胞周期蛋白 Rb 形成复合物（参考文献 5），并且有人认为 Rb 与 E2F 的这种结合使 E2F 失活（参考文献 5）。在这里，我们证明 Rb-E2F 是一种活性复合物，当与 E2F 位点结合时，会抑制其他启动子元件的活性，从而使转录沉默。我们认为该复合物抑制转录的能力是 Rb 功能不可或缺的一部分，并提供证据证明 E2F 在 Rb 活性形式不存在的情况下是一个正元件。研究表明，Rb 与 E2F 的结合取决于 Rb 的磷酸化状态（仅磷酸化不足的形式结合）5，并且 Rb 的磷酸化状态在细胞周期的进展过程中发生变化 6,7。因此，我们认为 E2F 位点随着 Rb 的磷酸化/去磷酸化循环在正元件和负元件之间交替。这种循环活动可能负责在细胞周期期间激活然后抑制基因。
ORIGINALLY E2F sites were identified as elements in the promoters of adenovirus early genes that are necessary for activation of these genes by the early protein E1a (ref. 1). E2F promoter elements have been shown to be important for transcriptional activation of several genes critical for progression through the cell cycle2-4. During the G1 phase of the cell cycle, the E2F protein forms a complex with the cell-cycle protein Rb (ref. 5) and it has been suggested that this binding of Rb to E2F inactivates E2F (ref. 5). Here we show that Rb-E2F is an active complex that, when bound to the E2F site, inhibits the activity of other promoter elements and thus silences transcription. We propose that the ability of this complex to inhibit transcription is integral to the function of Rb and provide evidence that E2F is a positive element in the absence of an active form of Rb. It has been shown that binding of Rb to E2F depends on the phosphorylation state of Rb (only the underphosphorylated form binds)5 and that the phosphorylation state of Rb changes during progression through the cell cycle6,7. We therefore suggest that the E2F site alternates between a positive and negative element with the phosphorylation/dephosphorylation cycle of Rb. This cyclic activity may be responsible for activating and then inhibiting genes during the cell cycle.