p53-independent Role of MDM2, TGFb Resistance and Cancer

tgf - β是一种功能性细胞因子，与肿瘤抑制有关。tgf - β可抑制正常细胞和早期肿瘤细胞的生长。然而，晚期肿瘤往往对TGFbeta变得难治，作为转移的适应性。幽默肿瘤中tgf - β耐药的机制尚未完全了解。我们的研究结果表明，致癌基因mdm2可能是通过p53独立机制（最有可能通过干扰Rb/3E2F功能）导致tgf - β耐药的原因。虽然MDM2和p53之间的相互作用已经被很好地表征，但对MDM2不依赖于p53的致癌活性知之甚少。本应用的目的是进一步探索在人类肿瘤发展过程中，MDM2在TGFbeta耐药和肿瘤发生中的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其赋予tgf - β抗性的能力至关重要。其次，我们将分析MDM2在TGFbeta抗性和肿瘤发生过程中对p53不依赖的活性的要求，这些肿瘤细胞系具有MDM2过表达的基因改变。最后，我们将利用反义MDM2抑制剂来检测TGFbeta耐药对人乳腺癌中MDM2表达的独立性。这些研究不仅将为肿瘤中导致tgfβ敏感性丧失的多种途径提供见解，而且还将揭示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.