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

tRNA与细胞色素c的相互作用在癌细胞凋亡中的作用

• 批准号: 8692304
• 负责人: Xiaolu Yang
• 金额: $ 17.4万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-05 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692304
• 关键词: ATP Synthesis Pathway; Adaptor Signaling Protein; Address; Amino Acids; Animal Model; Anticodon; Apoptosis; Apoptosis Regulator; Apoptotic; Binding; Biology; Cancer cell line; Caspase; Cell Death; Cell Death Process; Cells; Cessation of life; Clinical Trials; Combined Modality Therapy; Cues; Cytoplasm; DNA Damage; Electron Transport; Eukaryota; Event; Exhibits; Gene Expression; Genetic Code; Genetic Translation; Grant; Homeostasis; Hydrolysis; Immunity; In Vitro; Individual; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Mitochondria; Modality; Modeling; Normal Cell; Oncogene Activation; Onconase; Oxidative Phosphorylation; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Physiological Processes; Play; Proteins; RNA; Radiation therapy; Regulation; Resistance; Ribonucleases; Role; Testing; Toxic effect; Transfer RNA; Vertebrates; apoptotic protease-activating factor 1; base; cancer cell; cancer therapy; caspase-9; cellular development; cytochrome c; follow-up; human CASP4 protein; improved; in vivo; killings; mutant; neoplastic cell; new therapeutic target; preference; prevent; public health relevance; research study; tumor; tumor progression; tumorigenesis

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.

描述(申请人提供)：这个项目寻求表征转移RNA(TRNA)和细胞色素c(Cytc)之间的相互作用如何调节癌细胞的凋亡。TRNA和cytc是古老的分子，在生物学中具有基础作用。在健康细胞中，tRNA和cytc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，以及在氧化磷酸化过程中传输电子。细胞色素c也是固有的细胞凋亡途径中的决定性因素，而细胞凋亡途径对于预防癌症至关重要。W最近发现trna通过阻止细胞色素c的相互作用来抑制细胞周期蛋白c的促凋亡活性。 用半胱氨酸天冬氨酸酶激活剂APAF-1诱导细胞色素C的表达。我们将研究tRNA和cytc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新的治疗靶点的应用。我们的中心假设是，肿瘤细胞中高水平的tRNA有助于 细胞凋亡抵抗与肿瘤发生，靶向tRNA在肿瘤治疗中具有重要意义。我们提出了三个特定的目标：1)确定tRNA在内源性凋亡途径中的作用；2)研究肿瘤细胞对tRNA水解物的敏感性；3)确定tRNA特异性RNase Onconase和激活内源性凋亡途径的药物在肿瘤治疗中的联合作用。这里概述的实验将提高我们对tRNA在细胞死亡的基本过程中的理解，并将为癌症的治疗提供信息。