Dysregulation of programmed cell death is central to a number of human diseases. Insufficient cell death leads to cancer and some autoimmune diseases while excessive cell death contributes to a number of neurological disorders and AIDS. Overexpression of Bcl-2, an inhibitor of apoptosis, results from the chromosomal translocations characteristic of follicular lymphoma patients. Overexpression of a Bcl-2 family member, Bcl-XL, is frequently found in the Kaposi's sarcoma lesions of AIDS patients. Upregulation of one or more Bcl-2 family members in the late stage of tumor development is a common occurrence. However, the molecular mechanisms by which Bcl-2 family members regulate programmed cell death are only beginning to be understood. Again by unknown mechanisms Bcl-XL and Bcl-2 prevent the activation of caspases, a family of cysteine proteases that are key facilitators of apoptotic cell death. Recently, Bcl-2 family members were found to serve as caspase substrates. Caspases cleave Bcl-XL and Bcl-2 in the loop domain near the N-terminus which results in loss of the BH4 homology domain, a domain that is required for inhibition of cell death. As a result, cleavage of Bcl-XL and Bcl-2 by caspases converts these proteins from potent inhibitors of cell death to potent inducers of cell death. However, except for the universally conserved aspartate at the P1 position of the Bcl-XL cleavage sites, these sites do not resemble any other known caspase cleavage sites. Experiments are proposed to determine if posttranslational modification of the Bcl-XL cleavage sites by cellular kinases/phosphatases modulates the recognition of these site by caspases. The role of phosphorylation and the responsible kinases that regulate BcI-XL function during apoptosis will be studied in neurons and tumor cell lines. The protein domains required for the pro-death activity of cleaved Bcl-XL will be determined by extensive mutagenesis. Biochemical and functional analyses will be performed to explore the molecular mechanism behind this pro-apoptotic activity. These studies are expected to significantly advance our understanding of the molecular processes of programmed cell death which impact on a wide range of human disorders.
| Metz, Kyle A; Teng, Xinchen; Coppens, Isabelle et al. (2018) KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol 84:766-780 |
| Aouacheria, Abdel; Baghdiguian, Stephen; Lamb, Heather M et al. (2017) Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem Int 109:141-161 |
| Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2016) In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila. J Vis Exp : |
| Tang, Ho Lam; Tang, Ho Man; Hardwick, J Marie et al. (2015) Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosis. J Vis Exp : |
| Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2015) In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Rep 5:9015 |
| Teng, Xinchen; Hardwick, J Marie (2015) Cell death in genome evolution. Semin Cell Dev Biol 39:3-11 |
| Hartman, Adam L; Santos, Polan; O'Riordan, Kenneth J et al. (2015) Potent anti-seizure effects of D-leucine. Neurobiol Dis 82:46-53 |
| Aouacheria, Abdel; Combet, Christophe; Tompa, Peter et al. (2015) Redefining the BH3 Death Domain as a 'Short Linear Motif'. Trends Biochem Sci 40:736-748 |
| Hardwick, J Marie; Soane, Lucian (2013) Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol 5: |
| Teng, Xinchen; Dayhoff-Brannigan, Margaret; Cheng, Wen-Chih et al. (2013) Genome-wide consequences of deleting any single gene. Mol Cell 52:485-94 |
Showing the most recent 10 out of 48 publications
