Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic Ras
Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic Ras
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DOI：
10.1128/jvi.78.11.5934-5945.2004
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发表时间：
2004-06-01
影响因子：
5.4
通讯作者：
Krishna, S
中科院分区：
文献类型：
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作者：
Chakrabarti, O;Veeraraghavalu, K;Krishna, S
致癌高危人乳头瘤病毒(HPV)与主要的人类肿瘤样癌的进展有因果关系。一些研究已经确定了关键的E6和E7癌蛋白在上皮细胞永生化中的功能。这些癌基因在永生化上皮细胞向侵袭性肿瘤发展过程中的作用仍然知之甚少。在这里，我们建立了E6癌蛋白和丝裂原活化蛋白激酶(MAPK)信号的激活之间的新的联系，并表明该信号涉及Rap1。我们发现，激活的MAPK信号与非调控的Notch1信号协同作用，重建了HPV驱动的浸润性宫颈癌的特征。我们将我们的分析扩展到评估E6(氨基酸[AA]83)变异，该变异与侵袭性肿瘤有关。该变异体通过解除调控的Notch1信号来增强MAPK信号和协同转换。与E6不同的是，该变体出人意料地抑制了RAS介导的致癌转化。我们的数据显示，E6及其变异体激活MAPK信号的数量差异与与其他信号通路协同转化的差异有关，因此MAPK激活的阈值可能定义了其他信号通路在肿瘤发生中的许可条件。流行病学研究表明E6AA83变异在浸润性癌中的重要性；我们的数据支持该变异在人类宫颈肿瘤发生中的关键决定作用。这些观察，加上我们最近的数据显示，解除调控的Notch信号激活了磷脂酰肌醇3-激酶信号，加强了存在RAS非依赖性机制来通过经典的RAS效应器途径重建信号的可能性。
Oncogenically high-risk human papillomaviruses (HPVs) are causally associated with the progression of major human neoplasia-like cancers of the cervix. Several studies have defined functions of the key E6 and E7 oncoproteins in epithelial cell immortalization. The roles of these oncogenes in the progression of immortalized epithelial cells to invasive tumors are still poorly understood. Here, we establish a novel link between the E6 oncoprotein and activation of mitogen-activated protein kinase (MAPK) signaling and show that this signaling involves Rap1. We find that activated MAPK signaling cooperates with deregulated Notch1 signaling to recreate features of HPV-driven invasive cervical carcinomas. We extend our analysis to evaluate an E6 (amino acid [aa] 83) variant that has been linked to invasive tumors. The variant enhances MAPK signaling and cooperative transformation with deregulated Notch1 signaling. Unlike E6, this variant surprisingly inhibits oncogenic Ras-mediated transformation. Our data reveal that the quantitative differences in activation of MAPK signaling by E6 and its variant correlate with differences in cooperative transformation with other signaling pathways, thus suggesting that thresholds of MAPK activation may define permissive conditions for other signaling pathways in tumorigenesis. Epidemiological studies have suggested the importance of E6 aa 83 variants in invasive carcinomas; our data support a key deterministic role for this variant in human cervical tumorigenesis. These observations, along with our recent data showing that deregulated Notch signaling activates phosphatidylinositol 3-kinase signaling, strengthen the possibility of the existence of Ras-independent mechanisms to recreate signaling through classical Ras effector pathways.