The interaction between tRNA and cytochrome c in apoptosis of cancer cells

描述（由申请人提供）：该项目旨在表征转移RNA（tRNA）和细胞色素c（cyt c）之间的相互作用如何调节癌细胞的凋亡。tRNA和cyt c是在生物学中具有基本作用的古老分子。在健康细胞中，tRNA和cyt c的主要功能分别是通过将氨基酸连接到反密码子来解释遗传密码和在氧化磷酸化中运输电子。细胞色素c也是内在凋亡途径中的决定性参与者，这对于保护免受癌症至关重要。W最近发现，tRNA通过阻止相互作用抑制细胞色素c的促凋亡活性 与caspase激活剂Apaf-1的作用。我们将研究tRNA和细胞色素c在癌细胞死亡中的功能相互作用，并探索这种相互作用作为一种新的治疗靶点的效用。我们的中心假设是肿瘤细胞中高水平的tRNA有助于 细胞凋亡抗性和肿瘤发生，靶向tRNA在肿瘤治疗中是有益的。我们提出了三个具体目标：1）确定tRNA在内在凋亡途径中的作用; 2）研究癌细胞对tRNA水解的敏感性; 3）确定tRNA特异性RNase Onconase和肿瘤治疗中调用内在凋亡途径的药物的联合作用。这里概述的实验将提高我们对细胞死亡基本过程中tRNA的理解，并将为癌症治疗提供信息。

DESCRIPTION (provided by applicant): This project seeks to characterize how the interaction between transfer RNA (tRNA) and cytochrome c (cyt c) modulates apoptosis of cancer cells. tRNA and cyt c are ancient molecules with fundamental roles in biology. In healthy cells the major function of tRNA and cyt c are to interpret the genetic code by connecting amino acids to anticodons and to transport electrons in oxidative phosphorylation, respectively. Cyt c is also a defining player in the intrinsic apoptosis pathway, which is critical for protection from cancer. W recently found that tRNA inhibits the pro-apoptotic activity of cyt c by preventing the interaction of cyt c with the caspase activator Apaf-1. We will investigate the functional interaction between tRNA and cyt c in cancer cell death and to explore the utility of this interaction as a novel therapeutic target. Our central hypothesis is that high levels of tRNA in tumor cells contribute to apoptosis resistance and tumorigenesis, and targeting tRNA is beneficial in tumor therapy. We propose three specific aims: 1) Define the role of tRNA in the intrinsic apoptosis pathway; 2) Investigate the sensitivity of cancer cells to tRNA hydrolysis; and 3) Determine the combined effect of the tRNA-specific RNase Onconase and agents that invoke the intrinsic apoptosis pathway in tumor therapy. The experiments outlined here will improve our understanding of tRNA in the fundamental processes of cell death, and will inform therapies in cancer.