Functional Components of the Rb/E2F and p53 Pathways

描述（由申请人提供）： Rb/E2F 肿瘤抑制通路的正常功能在所有人类肿瘤中均受到损害。因此，其功能和调控是癌症研究至关重要和强烈关注的领域。 pRb 通过抑制 E2F 转录因子来控制细胞周期从 G1 期到 S 期的转变。 Rb/E2F 通路调节多种活动，对构成该通路的功能成分的研究将为癌症生物学提供有价值的见解。 为了更深入地了解 Rb/E2F 通路，我建议将该通路分解为 使用计算方法分析组成的功能成分，然后研究通路成分的功能、调节机制和临床意义之间的关联。此外，我还将阐明相互交织的 Rb/E2F 和 p53 通路之间的功能关系，从而对这些肿瘤抑制通路之间的复杂相互作用产生新的见解。为了研究这些问题，我将利用我之前开发的方法来分解途径并推断驱动其表达的转录调节蛋白。因此，该提案的目标是：（1）将Rb/E2F途径分解为一系列由可识别转录调节蛋白调节的独立功能途径成分，（2）评估Rb/E2F途径成分与已识别的细胞周期调节因子之间的对应关系，以及（3）识别连接相互交织的Rb/E2F（细胞周期起始）和p53（细胞凋亡）途径的成分。 这些研究将导致新方法的发展，为更深入地了解影响途径功能的精确成分提供机会，并阐明一般细胞环境中相互关联途径之间的功能联系，这是系统生物学的目标。最终，表征和测量通路活性各个方面的能力将有助于开发更加精细的个性化疗法。 与公众健康的相关性 Rb 是一种肿瘤抑制因子，在所有癌症中都功能失调，导致一系列不良反应 了解 E2F 蛋白带来的活动。我建议开发计算方法来识别这些活动并单独研究它们，而不是作为一个整体进行研究。我相信这将导致人们更深入地了解该途径的功能以及针对该途径的药物。

DESCRIPTION (provided by applicant): Normal function of the Rb/E2F tumor suppressor pathway is compromised in all human tumors. Therefore, its function and regulation are areas of critical importance and intense interest for cancer research. pRb controls the cell cycle transition from G1- to S-phase through its repression of the E2F transcription factors. The Rb/E2F pathway regulates a diverse set of activities, and an investigation into the functional components that comprise the pathway would provide valuable insight into the biology of cancer. To obtain a deeper understanding of the Rb/E2F pathway, I propose to decompose the pathway into its constituent functional components using a computational approach, and then to investigate the associations among the functions, regulatory mechanisms, and clinical significance of the pathway components. In addition, I will also elucidate the functional relationships between the intertwined Rb/E2F and p53 pathways, yielding novel insight into the complex interactions between these tumor suppressor pathways. To investigate these issues, I will leverage methods I previously developed to decompose pathways and to infer the transcriptional regulatory proteins that drive their expression. Thus, the goals of this proposal are: (1) to decompose the Rb/E2F pathway into a series of independently functional pathway components regulated by identifiable transcriptional regulatory proteins, (2) to evaluate the correspondence between the components of the Rb/E2F pathway and identified regulators of the cell cycle, and (3) to identify components that connect the intertwined Rb/E2F (cell cycle initiation) and p53 (apoptosis) pathways. These studies would lead to the development of novel methodologies that provide the opportunity to obtain a deeper understanding of the precise components that effect pathway functions, and elucidate the functional connections among the interrelated pathways in a general cellular context, a goal of systems biology. Ultimately, the ability to characterize and measure individual facets of pathway activity will facilitate the development of ever more finely tuned personalized therapeutics. RELEVANCE TO PUBLIC HEALTH Rb is a tumor suppressor that is dysfunctional in all cancers, leading to a cascade of various poorly understood activities brought about by the E2F proteins. I propose to develop computational methods to identify these activities and study them individually, instead of as a whole. I believe that this will lead to a deeper understanding of the function of this pathway, as well as the drugs that target it.