Glucocorticosteroids (GC) induce lymphocytolysis, a form of programmed cell death (PCD) or apoptosis, and are therefore among the most effective agents for treating lymphoid malignancies. This competing renewal application will test and refine a PCD model based on emerging evidence that depletion of an endoplasmic reticulum (ER) Ca2+ pool critical for cell growth and survival is a central, bcl-2-regulated step in the lymphocyte PCD pathway.
The first aim will investigate how bcl-2 and bcl-X1 inhibit PCD by testing two hypotheses: (i) that prevention of ER Ca2+ pool depletion by bcl-2 and bcl-X1 inhibits apoptosis; and (ii) that bcl-2 and bcl-X1 prevent ER Ca2+ pool depletion by regulating ion channels in the ER membrane.
The second aim will investigate what governs whether a cell recovers from ER Ca2+ pool depletion or undergoes apoptosis by testing two hypotheses: (i) that increased transcription of 'protective response genes; enables a cell to recover normal growth and maintain viability in the presence of a decreased ER Ca2+ pool; and, (ii) that GC repress transcription of 'protective response genes', preventing recovery of cell growth and leading to cell death in response to ER Ca2+ pool depletion.
The third aim will investigate how sustained ER Ca2+ pool depletion induces apoptosis by testing two hypotheses: (i) that a constitutively expressed endonuclease is confined to the ER until it is released into the nucleus in response to sustained ER Ca2+ pool depletion; and, (ii) that sustained ER Ca2+ pool depletion regulates transcription of 'suicide gene(s)'. In summary, the proposed research will provide novel insight into molecular mechanisms of PCD in lymphocytes by testing and refining a model that already has strong support based on work in this laboratory during the previous funding period.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042755-11
Application #
2007578
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-11-01
Project End
1999-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Ryder, Christopher; McColl, Karen; Zhong, Fei et al. (2012) Acidosis promotes Bcl-2 family-mediated evasion of apoptosis: involvement of acid-sensing G protein-coupled receptor Gpr65 signaling to Mek/Erk. J Biol Chem 287:27863-75
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Harr, Michael W; Rong, Yiping; Bootman, Martin D et al. (2009) Glucocorticoid-mediated inhibition of Lck modulates the pattern of T cell receptor-induced calcium signals by down-regulating inositol 1,4,5-trisphosphate receptors. J Biol Chem 284:31860-71
Rong, Yi-Ping; Barr, Paul; Yee, Vivien C et al. (2009) Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor. Biochim Biophys Acta 1793:971-8
Rong, Yi-Ping; Aromolaran, Ademuyiwa S; Bultynck, Geert et al. (2008) Targeting Bcl-2-IP3 receptor interaction to reverse Bcl-2's inhibition of apoptotic calcium signals. Mol Cell 31:255-65

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