Apoptosis is a type of cell death carried out by intrinsic cellular machinery. This machinery is often circumvented in cancer cells, which prevents cancer cells from killing themselves and causes cancer-cell resistance to anti-cancer drugs. The biochemical mechanisms of apoptosis have just begun to be discovered. To dissect these mechanisms, we developed a cell-free system that reproduces apoptosis in vitro. This system has provided biochemical evidence that caspases, a family of highly specific and closely related cysteine proteases, plays a central role in cell execution, the terminal stage of apoptosis. The identity, function, and regulation of those caspases directly involved in apoptosis are largely unknown. Using the cell-free system, we will biochemically identify caspases directly involved in apoptosis. The regulation of these caspases will be revealed (I) by identifying the mechanisms by which they are proteolytically processed and thus activated; (ii) by identifying how their function is inhibited by viral and cellular inhibitors of their function; and (iii) by identifying changes in their subcellular localization upon activation. The function of caspases in apoptosis will be investigated by identifying and characterizing their substrates. These studies will advance our understanding of the mechanisms a cell uses to kill itself and will help determine how these mechanisms can be manipulated to selectively induce cell death.
| On, Kin Fan; Jaremko, Matt; Stillman, Bruce et al. (2018) A structural view of the initiators for chromosome replication. Curr Opin Struct Biol 53:131-139 |
| Knott, Simon R V; Wagenblast, Elvin; Khan, Showkhin et al. (2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554:378-381 |
| Shamay, Yosi; Shah, Janki; I??k, Mehtap et al. (2018) Quantitative self-assembly prediction yields targeted nanomedicines. Nat Mater 17:361-368 |
| Tramentozzi, Elisa; Ferraro, Paola; Hossain, Manzar et al. (2018) The dNTP triphosphohydrolase activity of SAMHD1 persists during S-phase when the enzyme is phosphorylated at T592. Cell Cycle 17:1102-1114 |
| Arun, Gayatri; Diermeier, Sarah D; Spector, David L (2018) Therapeutic Targeting of Long Non-Coding RNAs in Cancer. Trends Mol Med 24:257-277 |
| Tarumoto, Yusuke; Lu, Bin; Somerville, Tim D D et al. (2018) LKB1, Salt-Inducible Kinases, and MEF2C Are Linked Dependencies in Acute Myeloid Leukemia. Mol Cell 69:1017-1027.e6 |
| Xu, Yali; Milazzo, Joseph P; Somerville, Tim D D et al. (2018) A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia. Cancer Cell 33:13-28.e8 |
| Huang, Yu-Han; Klingbeil, Olaf; He, Xue-Yan et al. (2018) POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev 32:915-928 |
| Livshits, Geulah; Alonso-Curbelo, Direna; Morris 4th, John P et al. (2018) Arid1a restrains Kras-dependent changes in acinar cell identity. Elife 7: |
| Tiriac, Hervé; Belleau, Pascal; Engle, Dannielle D et al. (2018) Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. Cancer Discov 8:1112-1129 |
Showing the most recent 10 out of 610 publications
