Characterization of epidermal stem cells: biology, carci

表皮干细胞的表征：生物学、癌症

• 批准号: 7327246
• 负责人: Raymond W Tennant
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7327246
• 关键词: Characterization; epidermal; stem; cells; biology

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.

癌症生物学实验室多年来一直使用v-Ha-ras转基因Tg.AC小鼠模型来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乳头状瘤的发展和ras转基因在毛囊表皮干细胞和祖细胞中的异位表达之间的潜在联系。由此，我们发现造血干细胞标志物CD 34在小鼠皮肤中的毛囊隆突角化细胞上唯一表达。表达CD 34的隆突细胞已被证明是缓慢循环和多能的，将它们鉴定为干细胞和祖细胞群体。由于CD 34定位于毛囊中的致癌物靶细胞上，我们检验了CD 34可能在皮肤肿瘤发展中具有动态功能的假设。使用CD 34 KO小鼠系，我们已经表明，CD 34在干细胞活化和乳头状瘤形成中发挥作用，使用皮肤肿瘤发生的两阶段模型。 CD 34+角质形成细胞的基因表达分析揭示了裂手/裂足1（Dss 1）中的转录因子的表达，其随后被证明在细胞中具有生长调节作用。我们已经确定，Dss 1介导的生长调节作用，通过直接结合与Rpn 3/S3亚基的19 S调节颗粒的蛋白酶体组装，具有重要意义的结合蛋白酶体的泛素化底物和随后的蛋白质降解。 为了了解肿瘤发展中的关键信号通路，我们产生了p19 ARFhetTgAChemi和p19 ARFnullTgAChemi小鼠，以探索Ha-ras和p19 ARF在皮肤肿瘤发展中的关系。p19 ARFnullTgAChem小鼠意外地在胃肠道中产生肿瘤，随后发现其为胃肠道间质瘤（GIST），其是人类胃肠道中最常见的间质肿瘤。该模型提供了独特的机会，研究GIST的生物学从早期浸润前病变的恶性。