Direct repression of the Mcl-1 promoter by E2F1
Direct repression of the Mcl-1 promoter by E2F1
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DOI：
10.1038/sj.onc.1205157
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发表时间：
2002-02-21
期刊：
影响因子：
8
通讯作者：
Cress, WD
中科院分区：
文献类型：
--
作者：
Croxton, R;Ma, YH;Cress, WD
E2 F1通过p53依赖性和p53非依赖性机制诱导细胞凋亡。p53非依赖性通路中的直接靶点仍然是谜;然而，该通路的诱导不需要E2 F1的反式激活结构域。使用p53激活缺陷的细胞，我们发现E2 F1有效地抑制Mcl-1 -抗凋亡Bcl-2家族成员的表达，其耗尽导致细胞凋亡。我们还表明，这种转录抑制是直接和依赖于E2 F1的DNA结合域，但不需要E2 F1的反式激活域。与E2 F1抑制Mcl-1的这种DNA结合要求一致，我们表明E2 F1在体外和体内都与Mcl-1启动子结合，并鉴定了E2 F1结合和抑制所需的启动子内的DNA元件（-143/ -117）。此外，组成型表达Mcl-1的细胞系对E2 F1介导的细胞凋亡具有抗性，这表明Mcl-1下调是p53非依赖性细胞凋亡过程中的必要事件。因此，我们确定了一个p53家族的E2 F1诱导的细胞凋亡，其中E2 F1直接抑制Mcl-1表达的独立机制。
E2F1 induces apoptosis via both p53-dependent and p53-independent mechanisms. The direct targets in the p53-independent pathway remain enigmatic; however, the induction of this pathway does not require the transactivation domain of E2F1. Using cells that are defective in p53 activation, we show that E2F1 potently represses the expression of Mcl-1 - an anti-apoptotic Bcl-2 family member whose depletion results in apoptosis. We also show that this transcriptional repression is direct and dependent upon E2F1's DNA-binding domain, but does not require the transactivation domain of E2F1. Consistent with this DNA binding requirement of E2F1 to repress Mcl-1, we show that E2F1 binds to the Mcl-1 promoter both in vitro and in vivo, and have identified the DNA element (- 143/ -117) within this promoter that is required for E2F1 binding and repression. Additionally, cell lines constitutively expressing Mcl-1 are resistant to E2F1-mediated apoptosis - suggesting that Mcl-1 downregulation is a necessary event in the p53-independent apoptotic process. Thus, we identify a p53 family-independent mechanism of E2F1-induced apoptosis in which E2F1 directly represses Mcl-1 expression.