Pro-oncogenic roles of apoptotic caspases

描述（由申请人提供）：细胞凋亡通常被认为是致癌作用的障碍，因为它可以清除不需要的或受损的细胞。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，特别是凋亡半胱氨酸蛋白酶在肿瘤发生中的作用。在这个项目中，我们将研究的假设，即非致死性caspase 3或7激活诱导基因组不稳定，以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。由于许多内源性和外部刺激都能激活凋亡的caspase，因此它将具有广泛的意义。此类刺激的实例包括暴露于电离辐射、UV、化学品和致癌基因表达（例如，myc）。半胱天冬酶在致癌作用中的促进作用将为这些不同的环境损伤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，研究半胱天冬酶3和7在辐射和其他应激诱导的遗传不稳定性和致癌作用中的作用。我们希望我们的研究提供一个全面的评估的作用，半胱天冬酶3和7通过诱导遗传不稳定性促进癌变。在完成该项目后，我们希望我们可以获得重要的见解凋亡半胱天冬酶在癌症发生中的作用。这些见解可能为未来的癌症预防策略提供新的靶点。

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.