Control of c-Myc Function by the Tumor Suppressor p19ARF

描述(申请人提供)：我们已经证明了p19ARF蛋白与c-Myc蛋白结合并共定位，包括外源性和内源性。ARF与c-Myc结合可抑制c-Myc反式激活靶基因，抑制c-Myc诱导的过度增殖和转化。此外，ARF并不抑制c-Myc靶基因的抑制，实际上似乎是INR介导的抑制所必需的，并增强了c-Myc诱导的细胞凋亡。ARF还可抑制c-Myc的蛋白分解。这一互动的进一步特征和功能相关性是本提案的重点。我们的假设是，ARF与c-Myc的直接相互作用选择性地调节c-Myc蛋白的活性。因此，失去这一重要的检查点控制将导致c-Myc功能的放松调控，导致过度增殖、转化和抑制细胞凋亡。为了验证这一假设，我们将执行以下具体目标。具体目的是研究c-Myc和ARF之间的生化相互作用。具体目标2将是确定ARF调节c-Myc活性的分子机制。具体目标3将是确定ARF与c-Myc相互作用的生物学作用。我们的新发现和在这些特定目的中提出的实验结果将对c-Myc、ARF和P53的功能产生重大影响。我们的发现已经影响了关于c-Myc分子功能的有争议的模型，并可能继续影响c-Myc在分子水平上如何发挥作用以诱导对细胞增殖、肿瘤发生和凋亡的如此强大的控制的研究过程。ARF抑制c-Myc诱导的转化，促进c-Myc诱导的细胞凋亡，对肿瘤治疗具有直接的治疗意义。

DESCRIPTION (provided by applicant): We have shown that p19ARF protein binds and colocalizes with c-Myc protein, both exogenously and endogenously. ARF binding to c-Myc inhibits c-Myc transactivation of target genes and c- Myc-induced hyperproliferation and transformation. Furthermore, ARF does not inhibit repression of c-Myc target genes and actually appears necessary for Inr-mediated repression and enhances c- Myc-induced apoptosis. ARF also inhibits the proteolysis of c-Myc. The further characterization and functional relevance of this interaction is the focus of this proposal. Our hypothesis is that direct ARF interaction with c-Myc selectively regulates the activity of c-Myc protein. Therefore, loss of this important checkpoint control would contribute to deregulation of c-Myc function leading to hyperproliferation, transformation and inhibition of apoptosis. To test this hypothesis the following specific aims will be performed. Specific Aim I will be to characterize the biochemical interaction between c-Myc and ARF. Specific Aim 2 will be to determine the molecular mechanism that mediates the regulation of c-Myc activity by ARF. Specific Aim 3 will be to determine the biological role of the interaction of ARF with c-Myc. Our novel findings and the results of experiments proposed in these specific aims will have major implications for the function of c-Myc, ARF and p53. Our findings have already impacted the controversial model on the molecular function of c-Myc and will likely continue to impact the course of c-Myc studies on how c-Myc functions at the molecular level to elicit such powerful control over cellular proliferation, tumorigenesis and apoptosis. Finally, the inhibition of c-Myc-induced transformation and enhancement of c-Myc-induced apoptosis by ARF has direct therapeutic significance for cancer treatment.