p53-independent Role of MDM2, TGFb Resistance and Cancer

MDM2、TGFb 耐药性和癌症的 p53 独立作用

• 批准号: 6624266
• 负责人: PEIQING SUN
• 金额: $ 32.97万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624266
• 关键词: antisense nucleic acid; athymic mouse; breast neoplasms; carcinogenesis; carcinogenesis inhibitor; cell line; oncogenes; transforming growth factors

TGFbeta is a functional cytokine that has been implicated in tumor suppression. The growth of normal cells and early stage tumor cells is inhibited by TGFbeta. However, late stage tumors often become refractory to TGFbeta, as an adaptation to metastasis. The mechanisms for TGFbeta resistance in humor tumors has not been completely understood. Our results indicate that an oncogene, mdm2, is a likely cause of TGFbeta resistance through a p53-independent mechanism, most likely by interference with the Rb/3E2F functions. While the interaction between MDM2 and p53 has been well characterized, little is known about the p53-independent oncogenic activity of MDM2. The goal of this application is to further explore the p53-independent roles of MDM2 in TGFbeta resistance and tumorigenesis during human tumor development. First, mutational analysis will be performed to determine which regions and activities of MDM2 are essential for it ability to confer TGFbeta resistance. Second, the requirement for the p53- independent activity of MDM2 in TGFbeta resistance and tumorigenesis will e analyzed in human tumor cell lines created with defined genetic alterations involving MDM2 over-expression. Finally, anti-sense MDM2 inhibitors will be used to examine the independence of TGFbeta resistance on MDM2 expression in human breast carcinomas. These studies will not only offer insights into the diverse pathways leading to the loss of TGFbeta sensitivity in tumors, but also reveal novel roles of MDM2 in tumorigenesis.

TGFBETA是一种与肿瘤抑制有关的功能性细胞因子。 TGFBETA抑制正常细胞和早期肿瘤细胞的生长。但是，后期肿瘤通常会成为TGFBETA的难治性，以适应转移。尚未完全了解幽默肿瘤中TGFBETA抗性的机制。我们的结果表明，癌基因MDM2可能是通过p53独立的机制引起TGFBETA抗性的原因，这很可能是由于干扰RB/3E2F函数的原因。尽管MDM2和p53之间的相互作用已经很好地表征了，但对MDM2的p53独立致癌活性知之甚少。该应用的目的是进一步探索MDM2在人类肿瘤发育过程中MDM2在TGFBETA抗性和肿瘤发生中的独立作用。首先，将进行突变分析以确定MDM2的哪些区域和活动对于赋予TGFBETA抗性的能力至关重要。其次，将MDM2在TGFBETA耐药性和肿瘤发生中的p53-独立活性的需求将在人类肿瘤细胞系中分析，该细胞系具有涉及MDM2过表达的确定遗传变化。最后，将使用抗敏感性MDM2抑制剂检查人类乳腺癌中TGFBETA耐药性对MDM2表达的独立性。这些研究不仅会提供有关导致肿瘤中TGFBETA敏感性丧失的多种途径的见解，而且还揭示了MDM2在肿瘤发生中的新作用。