Human papillomavirus E7 oncoprotein dysregulates steroid receptor coactivator 1 localization and function
Human papillomavirus E7 oncoprotein dysregulates steroid receptor coactivator 1 localization and function
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DOI：
10.1128/jvi.02497-05
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发表时间：
2006-07-01
影响因子：
5.4
通讯作者：
Munger, Karl
中科院分区：
文献类型：
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作者：
Baldwin, Amy;Huh, Kyung-Won;Munger, Karl
高危型人乳头瘤病毒（HPV）几乎存在于所有宫颈癌中。然而，大多数感染高危HPV的妇女不会患宫颈癌。因此，辅因子必须有助于宫颈癌的发展和进展。虽然许多研究表明类固醇激素作为辅助因子参与了宫颈肿瘤的发生和发展，但其促进宫颈癌发生的分子机制目前尚不清楚。这些观察结果使我们研究了新发现的高危HPV 16型（HPV 16）E7癌蛋白与类固醇受体共激活因子1（SRC-1）的相关性，SRC-1是类固醇激素信号传导的重要组成部分。HPV 16 E7与SRC-1转录复合物中的p300和p300/CBP相关因子（PCAF）相互作用。我们在这里证明，HPV 16 E7在体内和体外与SRC-1的关联独立于p300和PCAF。在白细胞介素-8启动子或含有多聚化合成雌激素反应元件的启动子控制下的荧光素酶报告基因构建体用于确定高危和低危HPV E7表达对SRC-1介导的转录的影响。此外，进行组蛋白乙酰转移酶（HAT）测定以确定HPV E7对SRC-1相关HAT活性的影响。这些实验表明，HPV 16 E7表达下调SRC-1介导的转录和SRC-1相关的HAT活性。SRC-1定位实验表明，SRC-1在高危和低危HPV E7蛋白存在下重新定位于细胞质。我们的数据表明，HPV E7蛋白通过与SRC-1的关联和重新定位来失调细胞依赖性基因表达。SRC-1的定位和功能失调的HPV E7可能提供深入了解的分子机制，类固醇激素作为辅助因子的诱导和宫颈肿瘤的进展。
High-risk human papillomaviruses (HPVs) are present in virtually all cervical carcinomas. However, the majority of women infected with high-risk HPVs do not develop cervical cancer. Therefore, cofactors must contribute to the development and progression of cervical cancer. Although numerous studies have implicated steroid hormones as cofactors in the initiation and progression of cervical neoplasia, the molecular mechanisms by which they contribute to cervical carcinogenesis are currently unknown. These observations led us to investigate a newly discovered association of the high-risk HPV type 16 (HPV16) E7 oncoprotein with steroid receptor coactivator 1 (SRC-1), an essential component of steroid hormone signaling. HPV16 E7 has been previously reported to interact with p300 and p300/CBP-associated factor (PCAF), members of some SRC-1 transcriptional complexes. We demonstrate here that HPV16 E7 associates in vivo and in vitro with SRC-1 independently of p300 and PCAF. Luciferase reporter constructs under the control of either the interleukin-8 promoter or a promoter containing multimerized synthetic estrogen response elements were used to determine the effect of high- and low-risk HPV E7 expression on SRC-1-mediated transcription. In addition, histone acetyltransferase (HAT) assays were performed to determine the effect of HPV E7 on SRC-1-associated HAT activity. These experiments reveal that HPV16 E7 expression down-regulates SRC-1-mediated transcription and SRC-1-associated HAT activity. SRC-1 localization experiments show that SRC-1 is relocalized to the cytoplasm in the presence of high- and low-risk HPV E7 proteins. Our data suggest that HPV E7 proteins dysregulate hormone-dependent gene expression by association with and relocalization of SRC-1. Dysregulation of SRC-1 localization and function by HPV E7 may provide insight into the molecular mechanisms by which steroid hormones act as cofactors in the induction and progression of cervical neoplasia.