Pro-oncogenic roles of apoptotic caspases

描述(由申请人提供)：细胞凋亡通常被认为是癌症发生的屏障，因为它在清除不想要的或受损的细胞方面起到了作用。然而，我们实验室最近的发现表明，我们需要重新研究细胞凋亡，特别是那些凋亡的半胱氨酸天冬氨酸酶在肿瘤发生中的作用。在这个项目中，我们将检验一种假说，即非致命性的caspase3或7激活会导致基因组不稳定，从而促进辐射和其他应激诱导的致癌作用。我们的假设是一个大胆的假设，与当前的范式背道而驰。这将具有广泛的意义，因为许多内源性和外部刺激都可以激活凋亡的caspase。这类刺激的例子包括暴露于电离辐射、紫外线、化学物质和癌基因表达(例如myc)。半胱氨酸天冬氨酸酶在癌症发生中的促进作用将为这些不同的环境侮辱如何导致癌症提供令人兴奋的新见解。我们将使用各种体外和体内模型，结合最先进的分子技术，研究caspase3和7在辐射和其他应激诱导的遗传不稳定和癌症发生中的作用。我们期望我们的研究能够全面评价caspase3和7在通过诱导遗传不稳定性促进肿瘤发生中的作用。项目完成后，我们希望能够对凋亡半胱氨酸天冬氨酸酶在肿瘤发生中的作用有重要的了解。这些见解可能会为未来的癌症预防策略提供新的目标。

DESCRIPTION (provided by applicant): Apoptosis is normally considered a barrier for carcinogenesis because of its roles in getting rid of unwanted or damaged cells. However recent discoveries in our laboratory suggest that we need to re-examine the roles of apoptosis, especially those of apoptotic caspases, in carcinogenesis. In this project, we will examine the hypothesis that non-lethal caspase 3 or 7 activation induces genomic instability to facilitate radiation and other stress-induced carcinogenesis. Our hypothesis is a bold one that goes against the current paradigm. It will have wide-ranging implications since many endogenous and external stimuli could activate apoptotic caspases. Examples of such stimuli include exposure to ionizing radiation, UV, chemicals, and oncogene expression (e.g., myc). A facilitative role for caspases in carcinogenesis would provide exciting new insights into how those diverse environmental insults cause cancer. We will use a variety of in vitro and in vivo models, in combination with state-of-the-art molecular technologies, to examine the roles of caspases 3&7 in radiation- and other stress-induced genetic instability and carcinogenesis. We expect our studies to provide a comprehensive evaluation of the roles of caspases 3&7 in promoting carcinogenesis through inducing genetic instability. Upon completion of the project, we hope we can gain significant insights into the roles of apoptotic caspases in carcinogenesis. Such insights may provide novel targets for future cancer prevention strategies.