p53-independent Role of MDM2, TGFb Resistance and Cancer

TGF β是一种与肿瘤抑制有关的功能性细胞因子。正常细胞和早期肿瘤细胞的生长受到TGF β的抑制。然而，作为对转移的适应，晚期肿瘤通常变得对TGF β难治。体液肿瘤中TGF β抵抗的机制尚未完全了解。我们的研究结果表明，癌基因，mdm2，是一个可能的原因TGF β抵抗通过p53-独立的机制，最有可能通过干扰Rb/3E2F功能。虽然MDM2和p53之间的相互作用已经得到很好的表征，但对MDM2的p53非依赖性致癌活性知之甚少。本申请的目的是进一步探索MDM2在人类肿瘤发展过程中TGF β抗性和肿瘤发生中的p53非依赖性作用。首先，将进行突变分析以确定MDM2的哪些区域和活性对于其赋予TGF β抗性的能力是必需的。其次，将在具有涉及MDM2过表达的确定的遗传改变的人肿瘤细胞系中分析MDM2在TGF β抗性和肿瘤发生中的p53非依赖性活性的需要。最后，反义MDM2抑制剂将用于检查TGF β抗性对人乳腺癌中MDM2表达的独立性。这些研究不仅将提供对导致肿瘤中TGF β敏感性丧失的不同途径的见解，还将揭示MDM2在肿瘤发生中的新作用。

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.