p53 and pathways of apoptosis

描述（由申请人提供）：p53蛋白在肿瘤抑制中起关键作用，代表细胞对内在和外在应激信号反应的关键介质。作为一种核转录因子，p53具有激活或抑制大量基因表达的能力。越来越多的证据表明，p53还具有非转录功能，在线粒体中直接作用于促进细胞凋亡。应激介导的p53活化的结果通常是生长停滞或细胞死亡（凋亡）。如何作出这种“决定”在该领域仍然是一个未解决的问题，并且一般被描述为由“细胞环境”或由促存活因子或促凋亡因子的平衡决定。因此，定义和表征控制这一重要决定并介导p53多种活动的关键细胞决定因素的目标在癌症生物学中至关重要。该研究项目的重点是我们最近发现的肝脏存活因子，胰岛素样生长因子结合蛋白1（IGFBP 1）和p53蛋白之间的功能联系。虽然在许多组织中，p53激活导致细胞死亡，但我们的数据表明，肝细胞中的p53也具有细胞保护作用。因此，主要目标将是研究p53/IGFBP 1反馈回路是否是介导正常和肿瘤性肝细胞的应激反应结果的关键途径的一部分。这些研究集中在与p53在应激反应中的作用方式相关的重要问题上，包括：线粒体p53对凋亡的贡献，p53功能的关键调节剂的鉴定和表征，以及决定应激激活的p53是否会促进生存或凋亡的因素。同时，他们解决了促生存/促再生蛋白IGFBP 1的细胞内作用机制。所获得的信息将提供一个必要的框架，需要更深入地了解影响正常和肿瘤肝细胞中细胞死亡信号传导机制的决定，这是合理设计治疗癌症和易患癌症的肝脏疾病的有效治疗策略所需的理解。

DESCRIPTION (provided by applicant): The p53 protein plays a critical role in tumor suppression, and represents a pivotal mediator of cellular responses to both intrinsic and extrinsic stress signals. As a nuclear transcription factor, p53 has the ability to activate, or repress, the expression a large number of genes. Accumulating evidence suggests that p53 also has a non-transcriptional function with a direct role at mitochondria in promoting apoptosis. The outcome of stress-mediated p53 activation generally is growth arrest or cell death (apoptosis). How this "decision" is made remains an unresolved question in the field, and is described in general terms as being determined by "cell context" or by the balance of prosurvival or proapoptotic factors. Thus, the goal of defining and characterizing key cellular determinants that control this important decision and mediate the diverse activities of p53 is of central importance in cancer biology. The focus of this research project centers on our very recent discovery of a functional link between a liver survival factor, insulin-like growth factor binding protein 1 (IGFBP1), and the p53 protein. While in many tissues, p53 activation leads to cell death, our data suggest that p53 in liver cells also has a cytoprotective role. Thus, a primary goal will be to investigate whether a p53/IGFBP1 feed-back circuit is part of a crucial pathway mediating the stress- response outcome of normal and neoplastic liver cells. These investigations center on important issues related to the ways p53 acts in response to stress, including: the contribution of mitochondrial p53 to apoptosis, the identification and characterization of critical modulators of p53 function, and the factors that determine whether stress-activated p53 will promote survival or apoptosis. In conjunction, they address the intracellular mechanism of action of the prosurvival/proregeneration protein, IGFBP1. The information obtained will provide an essential framework needed for development of greater insight into decisions that influence cell death signaling mechanisms in normal and neoplastic liver cells, an understanding that is needed for the rational design of effective therapeutic strategies in treating cancers and hepatic diseases that predispose to cancer.