REGULATION OF TUMOR DEVELOPMENT BY THE UBIQUITIN LIGASE ITCH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 尽管在筛查、早期发现和癌前息肉切除方面取得了进展，但结直肠癌仍然是所有美国人癌症死亡的第二大原因。 因此，许多研究致力于鉴定可能在advujant疗法中靶向并且可以容易地与当前使用的化疗方案组合的肿瘤特异性分子。 我们在这里提出的假设，ITCH，一个成员的Nedd 4样家族的泛素连接酶，是一个可行的候选新辅助治疗。 它已被证明是扩增的未分化甲状腺癌，并在体外抑制瘙痒增强化疗药物的作用，在各种癌细胞系，通过增强细胞凋亡，响应于药物治疗。 我们证明，瘙痒在体内肠腺瘤的启动中起着关键作用，缺乏瘙痒的ApcMin/+小鼠的肿瘤负荷减少了71%。 我们假设缺乏瘙痒的上皮细胞（特别是肿瘤细胞）对TXNIP、p63或p73介导的细胞凋亡更敏感。 我们将通过1）使用骨髓移植确定瘙痒在上皮和免疫系统中所起的作用来测试该假设; 2）使用条件性敲除方法描绘当ApcMin/+衍生的肿瘤对瘙痒丧失敏感时的窗口;和3）使用Q-PCR、蛋白质印迹和免疫组织化学分析来表征真实瘙痒靶标Txnip、p63和p73在正常组织、肿瘤组织和5-氟尿嘧啶处理的组织中的表达。 本文生成的数据将为开发这种新的潜在辅助治疗提供关键依据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Despite progress made in screening, early detection, and removal of precancerous polyps, colorectal cancer remains the second leading cause of cancer death in all Americans. Consequently, much research is dedicated to identifying tumor-specific molecules that might be targeted in advujant therapies and could be readily combined with currently used chemotherapy regimes. We present here the hypothesis that ITCH, a member of the Nedd4-like family of ubiquitin ligases, is a viable candidate for neoadjuvant therapies. It has been shown to be amplified in anaplastic thyroid carcinoma, and in vitro inhibition of Itch potentiates the effect of chemotherapeutic drugs in a variety of cancer cell lines by enhancing apoptosis in response to drug treatment. We demonstrate that Itch plays a critical role in the in vivo initiation of intestinal adenomas, and ApcMin/+ mice lacking Itch have a 71% reduction in their tumor burden. We hypothesize that epithelial cells lacking Itch (particularly tumor cells) are more sensitive to TXNIP-, p63-, or p73-mediated apoptosis. We will test this hypothesis by 1) determining the role played by Itch in both the epithelium and in the immune system using bone marrow transplantation; 2) delineating the window when ApcMin/+ -derived tumors are sensitive to the loss of Itch using a conditional knockout approach; and 3) characterizing the expression of bona fide Itch targets, Txnip, p63, and p73 in normal vs. tumor vs. 5-fluorouracil treated tissues using Q-PCR, Western blotting, and immunohistochemistry analysis. The data generated herein will provide critical rationale for developing this new potential adjuvant therapy.