The human adenovirus 5 L4 promoter is activated by cellular stress response protein p53.
The human adenovirus 5 L4 promoter is activated by cellular stress response protein p53.
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DOI：
10.1128/jvi.01924-13
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发表时间：
2013-11
影响因子：
5.4
通讯作者：
Leppard KN
中科院分区：
文献类型：
--
作者：
Wright J;Leppard KN
在腺病毒感染过程中，基因表达的重点以高度调控的方式从早期基因转移到晚期基因。两个基因产物，L4-22K和L4-33K，通过激活主要的晚期转录单位(MLTU)并调节其转录本的剪接来促进这种转换。L4-22K和L4-33K的表达最初是由最近发现的嵌入在MLTU中的L4启动子(L4P)驱动的，该启动子由早期和中期病毒因子E1a、E4Orf3和IVa2激活。在这里，我们表明，这个启动子也被细胞应激反应调节因子p53显著激活。外源性P53的表达激活了L4P，而内源性P53的缺失抑制了病毒激活剂对L4P的诱导。染色质免疫沉淀研究表明，P53与L4P结合，在5型腺病毒(Ad5)感染过程中，这种结合在感染后12h达到高峰，与L4P激活的感染周期相一致，然后随着MLP激活开始消失。在Ad5感染过程中，L4P的P53激活是显著的，因为在感染永生化或正常细胞之前P53的耗尽导致晚期基因表达的严重降低。由于L4P活性产物(L4-22K/33K)的作用，P53与L4P的结合是暂时的，它建立了一个负反馈环，确保L4P在晚期开始时的瞬时活性，并有助于从早期病毒基因表达到晚期病毒基因的有效切换。
During adenovirus infection, the emphasis of gene expression switches from early genes to late genes in a highly regulated manner. Two gene products, L4-22K and L4-33K, contribute to this switch by activating the major late transcription unit (MLTU) and regulating the splicing of its transcript. L4-22K and L4-33K expression is driven initially by a recently described L4 promoter (L4P) embedded within the MLTU that is activated by early and intermediate viral factors: E1A, E4 Orf3, and IVa2. Here we show that this promoter is also significantly activated by the cellular stress response regulator, p53. Exogenous expression of p53 activated L4P in reporter assays, while depletion of endogenous p53 inhibited the induction of L4P by viral activators. Chromatin immunoprecipitation studies showed that p53 associates with L4P and that during adenovirus type 5 (Ad5) infection, this association peaks at 12 h postinfection, coinciding with the phase of the infectious cycle when L4P is active, and is then lost as MLP activation commences. p53 activation of L4P is significant during Ad5 infection, since depletion of p53 prior to infection of either immortalized or normal cells led to severely reduced late gene expression. The association of p53 with L4P is transient due to the action of products of L4P activity (L4-22K/33K), which establish a negative feedback loop that ensures the transient activity of L4P at the start of the late phase and contributes to an efficient switch from early- to late-phase virus gene expression.