Apoptosis, or programmed cell death, is a process that multicellular organisms utilize to eliminate unwanted or damaged cells to maintain tissue homeostasis. It plays a critical role in development, immune responses and many other physiological events. Deregulation of apoptosis can lead to diseases such as cancer, immune disorders, and neurodegenerative diseases. Molecularly, apoptosis is executed by proteases known as caspases, and in mammals, a major caspase activation pathway is the cytochrome c-mediated pathway. In this pathway, caspase activation is initiated by cytochrome c release from mitochondria and subsequent assembly of a multimeric protein complex, the apoptosome, which is the central caspase activation machinery. Recently, we identified a new regulatory pathway that controls apoptosome activity. This regulatory pathway can be triggered by a synthetic compound, alpha-(trichloromethyl)-4-Pyridineethanol (PETCM), and the pathway is modulated by both the tumor suppressor PHAP (putative HLA-associated protein) and the oncoprotein prothymosin-alpha (ProT), indicating its potential involvement in oncogenesis. In this proposal, we will investigate the molecular mechanisms of the PETCM-initiated, apoptosome -regulatory pathway, including the mechanism by which PETCM initiates the pathway, and the mechanism by which PHAP stimulates apoptosome activity. In addition, we will determine the structural basis for the apoptotic and tumor suppressive activities of PHAP, and test whether the apoptotic activity of PHAP contributes to its tumor suppressive property. In conducting these studies, techniques of biochemistry, molecular biology, cell biology, and chemical biology will be used. This research will elucidate the molecular mechanisms of the death regulatory pathway and facilitate understanding of its physiological functions. This work should also shed light on designing novel cancer therapies by targeting this pathway. ? ?
| Xiong, Shunbin; Mu, Tianyang; Wang, Guowen et al. (2014) Mitochondria-mediated apoptosis in mammals. Protein Cell 5:737-49 |
| Gammoh, Noor; Florey, Oliver; Overholtzer, Michael et al. (2013) Interaction between FIP200 and ATG16L1 distinguishes ULK1 complex-dependent and -independent autophagy. Nat Struct Mol Biol 20:144-9 |
| Wang, Xinjiang; Jiang, Xuejun (2012) Mdm2 and MdmX partner to regulate p53. FEBS Lett 586:1390-6 |
| Huang, Guochang; Redelman-Sidi, Gil; Rosen, Neal et al. (2012) Inhibition of mycobacterial infection by the tumor suppressor PTEN. J Biol Chem 287:23196-202 |
| Gammoh, Noor; Lam, Du; Puente, Cindy et al. (2012) Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci U S A 109:6561-5 |
| Feldman, Taya; Kabaleeswaran, Venkataraman; Jang, Se Bok et al. (2012) A class of allosteric caspase inhibitors identified by high-throughput screening. Mol Cell 47:585-95 |
| Shi, Yuji; Paluch, Benjamin E; Wang, Xinjiang et al. (2012) PTEN at a glance. J Cell Sci 125:4687-92 |
| Ganley, Ian G; Wong, Pui-Mun; Gammoh, Noor et al. (2011) Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol Cell 42:731-43 |
| Nair, Usha; Jotwani, Anjali; Geng, Jiefei et al. (2011) SNARE proteins are required for macroautophagy. Cell 146:290-302 |
| Habrukowich, Cheryl; Han, David K; Le, Andrew et al. (2010) Sphingosine interaction with acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) regulates PP2A activity and cyclooxygenase (COX)-2 expression in human endothelial cells. J Biol Chem 285:26825-31 |
Showing the most recent 10 out of 16 publications
