Characterization of epidermal stem cells: biology, carci

癌症生物学实验室多年来一直使用v-Ha-ras转基因Tg。研究与皮肤肿瘤发展相关的分子和生物学事件。实验室的早期工作证明了在毛囊表皮干和祖细胞中ras转基因的异位表达与乳突瘤的发展之间存在潜在的联系。由此，我们发现造血干细胞标志物CD34在小鼠皮肤毛囊膨出角质形成细胞上是唯一表达的。表达cd34的凸起细胞已被证明是缓慢循环和多能的，将它们确定为干细胞和祖细胞群。由于CD34在毛囊中致癌靶细胞上的定位，我们验证了CD34在皮肤肿瘤发展中可能具有动态功能的假设。利用CD34KO小鼠细胞系，我们利用皮肤肿瘤发生的两阶段模型证明了CD34在干细胞激活和乳头瘤形成中发挥作用。

The Cancer Biology Laboratory has for many years used the v-Ha-ras transgenic Tg.AC mouse model to study the molecular and biological events associated with skin tumor development. Early work in the laboratory demonstrated a potential link between papilloma development and ectopic expression of the ras transgene in hair follicle epidermal stem and progenitor cells. From this, we discovered that the hematopoietic stem cell marker CD34 is uniquely expressed on hair follicle bulge keratinocytes in mouse skin. CD34-expressing bulge cells have been demonstrated to be both slowly cycling and multipotent, identifying them as a stem and progenitor cell population. Because of the localization of CD34 on carcinogen target cells in the hair follicle, we tested the hypothesis that CD34 may have a dynamic function in skin tumor development. Using a CD34KO mouse line, we have shown that CD34 plays a role in stem cell activation and papillomagenesis using the two-stage model of skin tumorigenesis. Gene expression analysis of CD34+ keratinocytes revealed expression of the Deleted in Split Hand/Split Foot 1 (Dss1), which has subsequently been shown to have a growth regulatory role in the cell. We have determine that Dss1 mediates its growth regulation effects through direct binding with the Rpn3/S3 subunit of the 19S regulatory particle of the proteasome assembly, with important implications in binding of the proteasome to ubiquitinylated substrates and subsequent protein degradation. To understand key signaling pathways in tumor development, we generated p19ARFhetTgAChemi and p19ARFnullTgAChemi mice to explore the relationship between Ha-ras and p19ARF in skin tumor development. The p19ARFnullTgAChem mice unexpectedly developed tumors in the gastrointestinal tract that were subsequently revealed to be Gastrointestinal Stromal Tumors (GIST), which are the most common mesenchymal tumor of the gastrointestinal tract in humans. This model offers the unique opportunity to study GIST biology from the early preinvasive lesion to malignancy.