Genther Williams Sybil M, Disbrow Gary L, Schlegel Richard, Lee Daekee, Threadgill David W, Lambert Paul F
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Cancer Res. 2005 Aug 1;65(15):6534-42. doi: 10.1158/0008-5472.CAN-05-0083.
Multicellular organisms rely on complex networks of signaling cascades for development, homeostasis, and responses to the environment. These networks involve diffusible signaling molecules, their receptors, and a variety of downstream effectors. Alterations in the expression or function of any one of these factors can contribute to disease, including cancer. Many viruses have been implicated in cancer, and some of these modulate cellular signal transduction cascades to carry out their life cycles. High-risk human papillomaviruses (HPVs), the causative agents of most cervical and anogenital cancers, encode three oncogenes. One of these, E5, has been postulated to transform cells in tissue culture by modulating growth factor receptors. In this study, we generate and characterize transgenic mice in which the E5 gene of the most common high-risk HPV, HPV16, is targeted to the basal layer of the stratified squamous epithelium. In these mice, E5 alters the growth and differentiation of stratified epithelia and induces epithelial tumors at a high frequency. Through the analysis of these mice, we show a requirement of the epidermal growth factor receptor for the hyperplastic properties of E5.
多细胞生物依靠复杂的信号级联网络进行发育、维持体内平衡以及对环境做出反应。这些网络涉及可扩散的信号分子、它们的受体以及各种下游效应器。这些因素中任何一个的表达或功能改变都可能导致疾病，包括癌症。许多病毒与癌症有关，其中一些病毒调节细胞信号转导级联以完成其生命周期。高危型人乳头瘤病毒（HPV）是大多数宫颈癌和肛门生殖器癌的病原体，编码三种癌基因。其中之一E5，据推测可通过调节生长因子受体在组织培养中使细胞发生转化。在本研究中，我们构建并鉴定了转基因小鼠，其中最常见的高危型HPV即HPV16的E5基因靶向于复层鳞状上皮的基底层。在这些小鼠中，E5改变了复层上皮的生长和分化，并高频诱导上皮肿瘤。通过对这些小鼠的分析，我们表明表皮生长因子受体对于E5的增生特性是必需的。
