Regulation of c-Myc Transcriptional Activity and Function

描述（由申请人提供）：c-Myc的关键作用是调节细胞周期进程和凋亡，这种调节的破坏已被证明可导致转化和肿瘤发生。初步数据显示，一种新的c-Myc结合蛋白B23调节c-Myc定位和c-Myc转录活性。B23还显著增强c- myc诱导的过度增殖和转化，同时调节c- myc介导的细胞凋亡。根据我们在本提案中提出的初步研究，我们的假设是B23与c-Myc的直接相互作用通过调节c-Myc的转录活性和定位来刺激肿瘤发生过程中c-Myc蛋白的致癌活性。我们认为，破坏这种相互作用可能是有效治疗结肠癌的基础。为了验证这一假设，我们将实现以下目标：1)表征c-Myc与B23蛋白的相互作用；2)确定B23蛋白介导c-Myc活性调控的分子机制；3)确定B23与c-Myc相互作用的生物学作用。我们还将根据我们的初步发现，开始测试抑制结肠癌细胞增殖的新疗法。这些研究将对理解c-Myc在细胞周期进程和凋亡以及癌症治疗中的功能具有重要意义。

DESCRIPTION (provided by applicant): A critical role of c-Myc is to regulate cell cycle progression and apoptosis and the disruption of this regulation has been shown to lead to transformation and tumorigenesis. Preliminary data has revealed a novel c-Myc binding protein, B23 that regulates c-Myc localization and c-Myc transcriptional activity. B23 also significantly enhances c-Myc-induced hyperproliferation and transformation, while also regulating c-Myc-mediated apoptosis. Based on our preliminary studies presented in this proposal, our hypothesis is that direct B23 interaction with c-Myc stimulates the oncogenic activities of c-Myc protein during tumorigenesis by regulating the transcriptional activity and localization of c-Myc. We propose that disruption of this interaction could be the basis of an effective treatment for colon cancer. To test this hypothesis, we will perform the following aims: 1) Characterize the interaction between c-Myc and B23 proteins, 2) Determine the molecular mechanism that mediates the regulation of c-Myc activities by B23 protein and 3) Determine the biological role of B23 interacting with c-Myc. We will also begin testing new treatments to inhibit colon cancer cell proliferation based on our preliminary findings. These studies will have major implications for understanding the function of c-Myc in cell cycle progression and apoptosis and in the treatment of cancer.