E1A activates transcription of p73 and noxa to induce apoptosis
E1A activates transcription of p73 and noxa to induce apoptosis
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DOI：
10.1074/jbc.m406661200
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发表时间：
2005-02-18
影响因子：
4.8
通讯作者：
Tavassoli, M
中科院分区：
文献类型：
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作者：
Flinterman, M;Guelen, L;Tavassoli, M
P73是p53蛋白家族的一员，通过转录激活一些参与细胞周期和凋亡控制的基因。在大量的原发性头颈癌中检测到p73的过表达，在已建立的细胞系中，这些细胞系都含有p53失活突变。p73过表达在头颈癌发病机制中的意义目前尚不清楚。我们已经证明，腺病毒5e1a在一组头颈部癌细胞系中的表达诱导了独立于p53状态的细胞凋亡。在这项研究中，我们研究了p73及其转录靶点在e1a介导的细胞凋亡诱导中的作用。E1A的表达导致TAp73启动子的显著激活，但对DeltaNp73启动子没有影响。ETA也增加了内源性TAp73 mRNA和蛋白的表达。缺乏p300和/或prb结合位点的E1A突变体显示激活TAp73启动子的能力降低。此外，TAp73启动子中e2f1结合位点的突变会破坏E1A的激活。重要的是，在几种p53缺失的癌细胞系中，表达E1A的13S异构体可显著诱导p53凋亡靶点Noxa。我们的研究结果表明，E1A激活p73和p53凋亡靶点Noxa可以在没有功能p53的情况下发生。这种激活可能在某些癌症中E1A诱导p53非依赖性细胞凋亡的机制中发挥关键作用，并可能为未来的癌症治疗提供途径。
p73, a member of the p53 family of proteins, transcriptionally activates a number of genes involved in the control of cell cycle and apoptosis. Overexpression of p73 was detected in a large number of primary head and neck cancers, and in the established cell lines examined, these all contained inactivating p53 mutations. The significance of p73 overexpression in the pathogenesis of head and neck cancer is currently unclear. We have shown that the expression of adenovirus 5 E1A in a panel of head and neck cancer cell lines induces apoptosis independently of their p53 status. In this study we examined the role of p73 and its transcriptional targets in E1A-mediated induction of apoptosis. E1A expression resulted in significant activation of the TAp73 promoter but had no effect on the alternative, DeltaNp73 promoter. ETA also increased expression of endogenous TAp73 mRNA and protein. E1A mutants lacking the p300-and/or pRB-binding sites showed reduced ability to activate the TAp73 promoter. Additionally, mutations in the E2F1-binding sites in the TAp73 promoter impaired activation by E1A. Importantly, expression of the 13S isoform of E1A substantially induced the p53 apoptotic target Noxa in several p53-deficient cancer cell lines. Our results indicate that E1A activation of p73 and the p53 apoptotic target Noxa can occur in the absence of a functional p53. This activation is likely to play a key role in the mechanism of p53-independent apoptosis induced by E1A in some cancers and may provide an avenue for future cancer therapies.