p53 induces the expression of its antagonist p73ΔN, establishing an autoregulatory feedback loop
p53 induces the expression of its antagonist p73ΔN, establishing an autoregulatory feedback loop
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DOI：
10.1038/sj.onc.1205584
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发表时间：
2002-07-18
期刊：
影响因子：
8
通讯作者：
Dobbelstein, M
中科院分区：
文献类型：
--
作者：
Kartasheva, NN;Contente, A;Dobbelstein, M
p53肿瘤抑制蛋白激活转录并诱导细胞死亡。p53的一个密切同源物，称为p73，以反式激活（TA）形式表达，诱导生长停滞和凋亡，非常像p53。然而，p73基因含有第二个启动子，引起p73 DeltaN的表达，p73 DeltaN是一种缺乏N-末端反式激活结构域的p73蛋白。我们发现p53在mRNA和蛋白水平上诱导p73 DeltaN的表达。克隆了调节人细胞中p73 DeltaN表达的启动子，发现其直接通过特定的DNA元件被p53和p73 TA激活。由此表达的p73 DeltaN蛋白与p53应答启动子DNA结合，与p53竞争DNA结合，拮抗p53对转录的激活，并阻止p53诱导的细胞死亡。此外，在剪接变体p73 DeltaNalpha内鉴定了转录阻遏物结构域。p73 δ N α和mdm2的组合比单独的p73 δ N α或mdm2更强地拮抗p53。通过反式显性片段阻断内源性p73 DeltaN或通过siRNA去除内源性p73 DeltaN，增加了含有野生型p53基因的细胞中p53应答启动子的活性。因此，通过p53诱导p73 Δ N表达建立了一个自动调节反馈环，该反馈环将细胞死亡的触发保持在严格控制之下。
The p53 tumor suppressor protein activates transcription and induces cell death. A close homologue of p53, termed p73, is expressed in transactivating (TA) forms that induce growth arrest and apoptosis much like p53. However, the p73 gene contains a second promoter, giving rise to the expression of p73DeltaN, a species of p73 proteins that lack the N-terminal transactivation domain. We show here that the expression of p73DeltaN is induced by p53 on the mRNA and protein level. The promoter that regulates p73DeltaN expression in human cells was cloned and found to be activated by p53, as well as by p73TA, directly through a specific DNA element. The p73DeltaN proteins, that are thereby expressed, bound to p53-responsive promoter DNA, competed with p53 for DNA binding, antagonized the activation of transcription by p53, and prevented p53-induced cell death. In addition, a transcriptional repressor domain was identified within the splicing variant p73DeltaNalpha. The combination of p73DeltaNalpha and mdm2 antagonized p53 more strongly than either p73Nalpha or mdm2 alone. Blocking endogenous p73DeltaN by a trans dominant fragment, or its removal by siRNA, increased the activity of a p53-responsive promoter in cells that contain a wild type p53 gene. Thus, the induction of p73DeltaN expression by p53 establishes an autoregulatory feedback loop that keeps the trigger of cell death under tight control.