This competing renewal application is for research into the mechanism of glucocorticosteroid induced apoptosis in lymphoma and leukemia cells. An in depth understanding of this mechanism at the molecular and cell biological level is essential to an understanding of how glucocorticoids work as therapeutic agents in lymphoid malignancies and how lymphoid malignancies become resistant to glucocorticoid-induced apoptosis. Using lymphoma and leukemia cell lines as a model system, this research focuses on two research themes that have arisen through work in this laboratory during the preceding funding period. One is focused on the role of proteasome-mediated c-Fos degradation in dexamethasone (DX)-induced apoptosis. This theme is based on the recent discovery that proteasome-mediated degradation of c-Fos is an early, Bc1-2-regulated step in DX induced apoptosis and that c-FosdeltaC, a c-Fos mutant that evades degradation by the proteasome, is a potent inhibitor of caspase activation and apoptosis. The other theme builds on evidence that calcium release from its intracellular reservoir in the endoplasmic reticulum (ER) is involved in mediating DX-induced apoptosis.
Aim 1 will investigate the mechanism of c-Fos degradation in DX- induced apoptosis, focusing on the role of the glucocorticoid receptor and c-Fos - c-Jun interaction in this process.
Aim 2 seeks to understand how c-Fos degradation contributes to apoptosis by investigating the mechanism by which the stable c- Fos mutant, c-FosdeltaC, inhibits apoptosis.
This aim will investigate the effect of c-FosdeltaC on glucocorticoid receptor activity and on AP-1-glucocorticoid receptor crosstalk. Also, this aim will identify genes regulated by c-FosdeltaC that function as apoptosis inhibitors.
Aim 3 will investigate the role of ER calcium release in DX induced apoptosis, determining how ER calcium release triggers apoptosis and the relationship between ER calcium release and other events in apoptosis, including proteasome-mediated c-Fos degradation and caspase activation.
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