Activation of c-Myc contributes to bovine papillomavirus type 1 E7-induced cell proliferation
Activation of c-Myc contributes to bovine papillomavirus type 1 E7-induced cell proliferation
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DOI：
10.1074/jbc.m306008200
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发表时间：
2003-10-31
影响因子：
4.8
通讯作者：
Chen, JJ
中科院分区：
文献类型：
--
作者：
Fan, XL;Liu, Y;Chen, JJ
人乳头瘤病毒（HPV）癌蛋白E7对肿瘤抑制基因pRB的灭活是HPV促进细胞生长的一种机制。牛乳头瘤病毒1型（BPV-1）E7不能有效结合pRB，但它是BPV-1完全转化鼠细胞所必需的。在本研究中，我们研究了BPV-1 E7诱导细胞增殖的机制。我们的研究表明，BPV-1 E7的表达诱导DNA合成，并刺激细胞进入S期在静止细胞。BPV-1 E7诱导的细胞增殖可发生在视网膜母细胞瘤基因（Rb）-null细胞中，这表明Rb-独立的机制。与该观察结果一致，BPV-1 E7不能有效地激活E2 F家族转录因子（E2 F）响应性启动子的转录。值得注意的是，c-Myc能够通过Rb/E2 F非依赖性途径诱导细胞在静止细胞中进入S期。值得注意的是，在BPV-1 E7表达细胞中c-Myc水平增加。此外，显性失活的c-Myc突变体的表达抑制BPV-1 E7诱导的DNA合成。与c-Myc可以下调p27并激活Cdk 2的观点一致，在BPV-1 E7表达细胞中，p27水平降低，而细胞周期蛋白A和细胞周期蛋白E相关激酶活性上调。这些研究表明c-Myc在BPV-1 E7诱导的细胞增殖中起重要作用。
Inactivation of the tumor suppressor pRB by the human papillomavirus (HPV) oncoprotein E7 is a mechanism by which HPV promotes cell growth. The bovine papillomavirus type 1 (BPV-1) E7 does not bind pRB efficiently yet is required for full transformation of murine cells by BPV-1. In the present study, we investigated the mechanism of BPV-1 E7-induced cell proliferation. Our studies indicate that expression of BPV-1 E7 induces DNA synthesis and stimulates cells to enter S phase in quiescent cells. The induction of cell proliferation by BPV-1 E7 can occur in the retinoblastoma gene (Rb)-null cells, suggesting an Rb-independent mechanism. Consistent with this observation, BPV-1 E7 does not efficiently activate the transcription of the E2F family of transcription factors (E2F)-responsive promoters. Notably, c-Myc is able to induce cells to enter S phase in quiescent cells through an Rb/E2F-independent pathway. Significantly, c-Myc levels are increased in BPV-1 E7-expressing cells. Moreover, expression of a dominant negative c-Myc mutant inhibited BPV-1 E7-induced DNA synthesis. Consistent with the notion that c-Myc could down-regulate p27 and activate Cdk2, p27 level is decreased while both cyclin A and cyclin E-associated kinase activities are up-regulated in BPV-1 E7-expressing cells. These studies indicate an important role for c-Myc in BPV-1 E7-induced cell proliferation.