由鼠乳头瘤病毒 (MmuPV1) 编码的 E6 蛋白对于 MmuPV1 诱导的皮肤病至关重要。我们之前的工作通过亲和纯化/质谱分析鉴定了 MmuPV1 E6 和 E7 的许多细胞相互作用伙伴。这些研究表明，MmuPV1 E6 通过多种分子机制（包括抑制 NOTCH 和 TGF-β 信号传导）有效抑制角质形成细胞分化。在这里，我们报告说，MmuPV1 E6 在其天然宿主细胞（小鼠角质形成细胞）中表达时具有其他重要的致癌活性，包括增加增殖、克服密度介导的生长停滞以及在生长因子供应有限的条件下增殖。对表达 MmuPV1 E6 的小鼠角质形成细胞进行的无偏蛋白质组学/转录组学分析证实了其对这些细胞过程的影响，并揭示其中一些影响可能部分是通过其上调 E2F 活性来介导的。我们的分析还表明，MmuPV1 E6 可能会改变其他癌症标志，包括逃避生长抑制剂、抑制免疫反应、抵抗细胞死亡以及 DNA 损伤反应的改变。总的来说，我们的结果表明，MmuPV1 E6 是 MmuPV1 天然宿主细胞（小鼠角质形成细胞）多种癌症特征的主要驱动因素。重要性小家鼠乳头瘤病毒 1 (MmuPV1) E6 和 E7 蛋白是 MmuPV1 诱导的疾病所必需的。我们对 MmuPV1 E6 活性的理解基于亲和纯化/质谱研究，其中鉴定了 MmuPV1 E6 的细胞相互作用伴侣，这些研究表明 MmuPV1 E6 可以通过多种机制抑制角质形成细胞分化。我们报告MmuPV1 E6编码额外的活性，包括诱导增殖、抵抗密度介导的生长停滞以及减少对外源生长因子的依赖。蛋白质组学和转录组学分析提供的证据表明，MmuPV1 E6 增加了许多促进细胞增殖和其他癌症特征的细胞蛋白的表达和稳态水平。这些结果表明 MmuPV1 E6 是 MmuPV1 诱导的发病机制的主要驱动因素。

The E6 protein encoded by the murine papillomavirus (MmuPV1) is essential for MmuPV1-induced skin disease. Our previous work has identified a number of cellular interacting partners of MmuPV1 E6 and E7 through affinity purification/mass spectrometry analysis. These studies revealed that MmuPV1 E6 potently inhibits keratinocyte differentiation through multiple molecular mechanisms including inhibition of NOTCH and TGF-β signaling. Here, we report that MmuPV1 E6 has additional important oncogenic activities when expressed in its natural host cells, mouse keratinocytes, including increasing proliferation, overcoming density-mediated growth arrest, and proliferation under conditions of limited supply of growth factors. Unbiased proteomic/transcriptomic analyses of mouse keratinocytes expressing MmuPV1 E6 substantiated its effect on these cellular processes and divulged that some of these effects may be mediated in part through it upregulating E2F activity. Our analyses also revealed that MmuPV1 E6 may alter other cancer hallmarks including evasion of growth suppressors, inhibition of immune response, resistance to cell death, and alterations in DNA damage response. Collectively, our results suggest that MmuPV1 E6 is a major driver of multiple hallmarks of cancer in MmuPV1's natural host cells, mouse keratinocytes.IMPORTANCEThe Mus musculus papillomavirus 1 (MmuPV1) E6 and E7 proteins are required for MmuPV1-induced disease. Our understanding of the activities of MmuPV1 E6 has been based on affinity purification/mass spectrometry studies where cellular interacting partners of MmuPV1 E6 were identified, and these studies revealed that MmuPV1 E6 can inhibit keratinocyte differentiation through multiple mechanisms. We report that MmuPV1 E6 encodes additional activities including the induction of proliferation, resistance to density-mediated growth arrest, and decreased dependence on exogenous growth factors. Proteomic and transcriptomic analyses provided evidence that MmuPV1 E6 increases the expression and steady state levels of a number of cellular proteins that promote cellular proliferation and other hallmarks of cancer. These results indicate that MmuPV1 E6 is a major driver of MmuPV1-induced pathogenesis.