The overall goal of this proposal is to test the hypothesis that the susceptibility of cells to apoptosis induction is regulated by endogenous stress responses induced in response to perturbation or organelle function. The immediate focus is on the stress response triggered by thapsigargin-mediated depletion of the endoplasmic reticulum (ER) calcium pool. This stress response includes transcriptional induction of three resident ER calcium-binding proteins: Grp78, Grp94 and calreticulin. Signaling mechanisms that either mediate or repress the ER stress response and the role of the ER stress response in determining the susceptibility of cells to apoptosis will be investigated. The rationale for experiments planned in this proposal is based on evidence that a deficient ER stress response accounts for the unusual susceptibility of WEH17.2 mouse lymphoma cells to apoptosis, and that the deficient ER stress response in this cell line is due to proteasome-mediated degradation of c-Fos. The proposal has four specific aims: (1) Investigate the roles of c-Fos and c-Jun in mediating and/or repressing the ER stress response; (2) Use somatic cell hybridization to investigate the mechanism of ER stress response deficiency in WEH17.2 cells; (3) Use a functional selection strategy to identify cDNAs encoding proteins that mediate or repress the ER stress response; (4) Investigate the role of the ER stress response in regulating cellular susceptibility to apoptosis induction. Knowledge gained through this proposal will serve as a basis for investigating the role of endogenous cellular stress responses in determining the sensitivity of different types of cancer to apoptosis-inducing chemotherapeutic agents. Moreover, signaling pathways that mediate endogenous stress responses, once identified, will be potential targets of novel therapeutics designed to abrogate cellular protective mechanisms, thereby reducing the growth and metastatic potential of tumor cells, and increasing the sensitivity of tumor cells to chemotherapy-induced apoptosis.
| Wang, Zhengqi; Malone, Michael H; Thomenius, Michael J et al. (2003) Dexamethasone-induced gene 2 (dig2) is a novel pro-survival stress gene induced rapidly by diverse apoptotic signals. J Biol Chem 278:27053-8 |
| Unkila, M; McColl, K S; Thomenius, M J et al. (2001) Unreliability of the cytochrome c-enhanced green fluorescent fusion protein as a marker of cytochrome c release in cells that overexpress Bcl-2. J Biol Chem 276:39132-7 |
| He, H; McColl, K; Distelhorst, C W (2000) Involvement of c-Fos in signaling grp78 induction following ER calcium release. Oncogene 19:5936-43 |
