The development of tumors involves genetic mutations leading to changes in the control of tissue differentiation and homeostasis.  Important in this process are modifications in the control of the process of cellular suicide (programmed cell death).  Many tumor cells are resistant to intrinsic and extrinsic death stimuli, probably due to impaired death pathways in these cells.  One of hallmarks of cancer is the inhibition of programmed cell death.  Intracellular organelles possess sensors that detect specific cell death-inducing signals and activate different signal transduction pathways.  Although a lot of attention has been focused on the death pathway initiated from mitochondria, relatively little is known about the involvement of the endoplasmic reticulum (ER) during programmed cell death.  Experiments in this project are designed to elucidate the detailed molecular mechanisms regulating the ER-dependent cell death signaling pathways.  The following specific aims are proposed:

1. Investigate the mechanisms of disruption of the ER membrane during cell death.  The release of proteins that normally reside in the ER lumen into the cytosol during cell death will be studied.  How Bcl-2 proteins modulate ER membrane integrity also will be examined.
2. Study the death signaling pathways mediated by released ER lumen proteins.  The profile of released ER lumen proteins in response to different death stimuli will be characterized.  Involvement of the released ER lumen proteins in death regulation will be investigated.
3. Examine how the ER-specific death pathway interacts with the mitochondria-dependent death signaling pathway.  The sequential disruption of the ER and mitochondria membrane upon treatment with various death signals will be investigated.  The potential effect of death-inducing factors released from one organelle on membrane integrity of another organelle will be studied in vitro.

By carrying out the proposed experiments, we hope to better understand the detailed molecular mechanisms of the regulation of the ER-dependent cell death pathways.  We expect that data provided by this study will contribute to the development of new cancer treatments.