The overall objective of this project is to elucidate the mechanisms that control the activation of caspase-9. Caspase-9 is a major initiator caspase in mammalian cells. It exists in healthy cells as a latent precursor and becomes activated in response to a wide range of cell-intrinsic apoptosis stimuli such as developmental lineage information, oncogene activation, DNA damage, and nutritional deprivation. The intrinsic apoptosis pathway that activates caspase-9 is the major mechanism by which the formation of tumor cells is prevented in the first place, and by which tumor cells are killed by chemo- and radiation therapy. The activation of caspase- 9 occurs in a large cytosolic complex known as the apoptosome, the formation of which is triggered by the release of mitochondrial cytochrome c to the cytosol and the subsequent binding of cytochrome c to Apaf-1. This binding enables Apaf-1 to assemble into the heptameric apoptosome, which recruits procaspase-9 and permits its auto-activation. Previous studies by us and others demonstrated that the activation of initiator caspases is induced by their oligomerization. We will determine the mechanism for oligomerization-induced procaspase-9 activation (Aim 1). In addition, we found that tRNAs inhibit caspase-9 activation through direct interaction with cytochrome c and preventing the formation of the apoptosome. We will determine this important function of tRNAs which is beyond their well-established role in the transmission of genetic information. We will also examine this function of tRNAs in apoptosis resistance of tumor cells (Aim 2). Finally, the activation of caspase-9 in the apoptosome is inhibited by the inhibitor of apoptosis proteins (IAPs). This inhibitory effect of IAPs is countered during apoptosis by mitochondrial IAP-binding proteins. Compounds mimicking the effect of IAP-binding proteins show promise in tumor therapy. We recently identified a novel IAP- interacting protein residing in mitochondria. We will elucidate the role of this protein in caspase-9 activation (Aim 3). These three aims represent a concerted effort to elucidate the intricate control of caspase-9 activation at multiple levels. We believe that they will help the development of more effective treatments for apoptosis- related diseases, particularly cancer.
Apoptosis is critical for development and for protection against cancer. The intrinsic/mitochondrial pathway is a major apoptosis pathway in mammalian cells, which leads to the activation of caspase-9 and subsequent cell death. In this proposal, we plan to study the regulation of caspase-9 activation. We believe that this study will further the understanding of the intrinsic apoptosis pathway and have practical implications for treating diseases related to this pathway, including cancer, autoimmune disorders, and immunodeficiency.
| Liu, Cuiping; Stonestrom, Aaron J; Christian, Thomas et al. (2016) Molecular Basis and Consequences of the Cytochrome c-tRNA Interaction. J Biol Chem 291:10426-36 |
| Guo, Lili; Prall, Wil; Yang, Xiaolu (2016) Assays for the Degradation of Misfolded Proteins in Cells. J Vis Exp : |
| Guo, Lili; Giasson, Benoit I; Glavis-Bloom, Alex et al. (2014) A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol Cell 55:15-30 |
| Hou, Ya-Ming; Yang, Xiaolu (2013) Regulation of cell death by transfer RNA. Antioxid Redox Signal 19:583-94 |
| Du, Wenjing; Jiang, Peng; Mancuso, Anthony et al. (2013) TAp73 enhances the pentose phosphate pathway and supports cell proliferation. Nat Cell Biol 15:991-1000 |
| Chu, Y; Yang, X (2011) SUMO E3 ligase activity of TRIM proteins. Oncogene 30:1108-16 |
| Jiang, Peng; Du, Wenjing; Wang, Xingwu et al. (2011) p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat Cell Biol 13:310-6 |
| Mei, Yide; Hahn, Allison Alcivar; Hu, Shimin et al. (2011) The USP19 deubiquitinase regulates the stability of c-IAP1 and c-IAP2. J Biol Chem 286:35380-7 |
| Mei, Yide; Yong, Jeongsik; Liu, Hongtu et al. (2010) tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell 37:668-78 |
| Mei, Yide; Stonestrom, Aaron; Hou, Ya-Ming et al. (2010) Apoptotic regulation and tRNA. Protein Cell 1:795-801 |
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