Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: Evidence of a corepressor/coactivator exchange
Cyclooxygenase-2 transcription is regulated by human papillomavirus 16 E6 and E7 oncoproteins: Evidence of a corepressor/coactivator exchange
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DOI：
10.1158/0008-5472.can-06-4273
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发表时间：
2007-04-15
期刊：
影响因子：
11.2
通讯作者：
Dannenberg, Andrew J.
中科院分区：
文献类型：
--
作者：
Subbaramaiah, Kotha;Dannenberg, Andrew J.
环氧合酶(COX-2)在人乳头瘤病毒(HPV)诱导的疾病中过表达，包括宫颈癌。虽然HPVE6和E7癌蛋白与宫颈癌的发生有关，但它们对COX-2基因表达的影响尚不清楚。在表达HPV16E6和E7的宫颈癌细胞(CaSki和SIHA)中，与未感染的宫颈癌细胞(C33A)相比，COX-2mRNA、蛋白和前列腺素E-2合成水平增加。HPV16E6和E7癌蛋白通过激活表皮生长因子受体(EGFR)-RAS丝裂原活化蛋白激酶途径诱导COX-2转录。有趣的是，HPV16癌蛋白刺激了EGFR信号，部分是通过诱导EGFR配体双调节蛋白的释放来实现的。HPV16E6和E7的诱导作用是通过增强激活蛋白-1与COX-2启动子的环磷酸腺苷(CAMP)反应元件(-59/-53)结合而实现的。同时还研究了共激活子和辅阻遏子在HPV16E6和E7介导的COX-2诱导中的潜在作用。染色质免疫沉淀分析表明，E6和E7癌蛋白诱导磷酸化的c-jun、c-Fos、UbcH5和cAMP反应元件结合蛋白/p300重新聚集到COX-2启动子。相反，E6和E7抑制组蛋白去乙酰化酶3-核受体辅阻遏物(NCoR)复合体与COX-2启动子的结合。此外，NCoR的过表达阻断了E6和E7对COX-2启动子的刺激。综上所述，这些结果表明，HPV16E6和E7癌蛋白通过诱导辅抑制子/辅活化子交换来刺激COX-2的转录。据我们所知，这项研究还提供了第一个证据，证明NCoR可以作为COX-2基因表达的抑制因子。
Cyclooxygenase (COX-2) is overexpressed in human papillomavirus (HPV)-induced diseases, including cervical cancer. Although HPV E6 and E7 oncoproteins have been causally linked to cervical carcinogenesis, their effects on COX-2 gene expression are unknown. Increased levels of COX-2 mRNA, protein, and prostaglandin E-2 synthesis were detected in HPV16 E6- and E7-expressing cervical cancer cells (CaSki and SiHa) compared with an uninfected cervical cancer cell line (C33A). HPV16 E6 and E7 oncoproteins induced COX-2 transcription by activating the epidermal growth factor receptor (EGFR)-Ras mitogen-activated protein kinase pathway. Interestingly, HPV16 oncoproteins stimulated EGFR signaling, in part, by inducing the release of amphiregulin, an EGFR ligand. The inductive effects of HPV16 E6 and E7 were mediated by enhanced binding of activator protein-1 to the cyclic AMP (cAMP)-responsive element (-59/-53) of the COX-2 promoter. The potential contribution of coactivators and corepressors to HPV16 E6- and E7-mediated induction of COX-2 was also investigated. Chromatin immunoprecipitation assays indicated that E6 and E7 oncoproteins induced the recruitment of phosphorylated c-Jun, c-Fos, UbcH5, and cAMP-responsive element binding protein-binding protein/p300 to the COX-2 promoter. In contrast, E6 and E7 inhibited the binding of the histone deacetylase 3-nuclear receptor corepressor (NCoR) complex to the COX-2 promoter. Moreover, overexpression of NCoR blocked E6- and E7-mediated stimulation of the COX-2 promoter. Taken together, these results indicate that HPV16 E6 and E7 oncoproteins stimulated COX-2 transcription by inducing a corepressor/coactivator exchange. To our knowledge, this study also provides the first evidence that NCoR can function as a repressor of COX-2 gene expression.