Three unrelated viral transforming proteins (vIRF, EBNA2, and E1A) induce the MYC oncogene through the interferon-responsive PRF element by using different transcription coadaptors (Retracted article. See vol 98, pg 12313, 2001)
Three unrelated viral transforming proteins (vIRF, EBNA2, and E1A) induce the MYC oncogene through the interferon-responsive PRF element by using different transcription coadaptors (Retracted article. See vol 98, pg 12313, 2001)
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DOI：
10.1073/pnas.96.20.11566
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发表时间：
1999-09-28
影响因子：
11.1
通讯作者：
Moore, PS
中科院分区：
文献类型：
--
作者：
Jayachandra, S;Low, KG;Moore, PS
卡波西肉瘤相关疱疹病毒vIRF是一种病毒转录因子，可抑制干扰素信号传导并转化NIH 3T3细胞，但不结合干扰素刺激反应元件（ISRE） DNA序列。本研究表明，vIRF诱导MYC原癌基因是细胞转化所必需的，并且vIRF通过称为浆细胞瘤抑制因子（PRF）元件的ISRE序列中的特异性启动子相互作用将MYC转录增加15倍。这些作用对环己亚胺具有抗性，但被显性阴性ISRE结合蛋白抑制，这表明vIRF与PRF元件上的细胞辅助因子一起作用，直接反激活MYC。coadaptor creb结合蛋白（CBP）与vIRF结合并协同MYC的反激活，但出乎意料的是，密切相关的组蛋白乙酰转移酶p300和P/CAF有效抑制vIRF的反激活。在预测其他干扰素抑制病毒转化蛋白行为相似的基础上，我们发现eb病毒诱导的核抗原2 （EBNA2）也结合p300/CBP，并且EBNA2和腺病毒E1A都通过PRF元件反激活MYC，对于E1A， P/CAF共同激活MYC，而p300和CBP均抑制E1A的反激活。对于EBNA2， P/CAF和CBP共同激活MYC启动子，而p300抑制EBNA2的转激活。这些发现表明，病毒转化蛋白可以通过共接头相互作用激活和抑制转录，在一些启动子中，CBP和p300彼此具有以前未被识别的竞争性拮抗作用。虽然这三种病毒蛋白都针对相同的启动子元件，但它们都有不同的共适配器使用谱。这些发现与细胞MYC抑制在先天免疫和细胞增殖控制中发挥作用是一致的。
Kaposi sarcoma-associated herpesvirus vIRF is a viral transcription factor that inhibits interferon signaling and transforms NIH 3T3 cells, but does not bind interferon-stimulated response element (ISRE) DNA sequences. Here me show that induction of the MYC protooncogene is required for cell transformation by vIRF, and that vIRF increases MYC transcription up to 15-fold through specific promoter interactions at an ISRE sequence called the plasmacytoma repressor factor (PRF) element. These effects are resistant to cycloheximide but are inhibited by a dominant-negative ISRE binding protein, indicating that vIRF acts together with a cellular cofactor at the PRF element to directly transactivate MYC, The coadaptor CREB-binding protein (CBP) binds vIRF and synergizes transactivation of MYC, but, unexpectedly, closely related histone acetyltransferases p300 and P/CAF potently suppress vIRF transactivation. On the basis of the prediction that other interferon-inhibiting viral transforming proteins behave similarly, we found that Epstein-Barr virus-induced nuclear antigen 2 (EBNA2) also binds p300/CBP, and that both EBNA2 and adenovirus E1A transactivate MYC through the PRF element, For E1A, P/CAF coactivates MYC, whereas both p300 and CBP suppress E1A transactivation. For EBNA2, both P/CAF and CBP coactivate the MYC promoter, whereas p300 suppresses EBNA2 transactivation. These findings demonstrate that viral transforming proteins can activate as well as inhibit transcription through coadaptor interactions, At some promoters CBP and p300 have previously unrecognized, competitive antagonism to each other. While all three viral proteins target the same promoter element, each has a different coadaptor use profile. These findings are consistent with cellular MYC repression playing a role in innate immunity as well as in control of cell proliferation.