The BCR-Abl oncoprotein is directly linked to the pathogenesis of chronic myeloid leukemia and a subset of acute lymphocytic leukemias. BCR-Abl promotes tumorigenesis by increasing cellular proliferation and inhibiting cell death (apoptosis). However, the mechanism by which BCR-Abl prevents apoptosis remains largely unknown. In response to DNA damage, apoptotic signaling pathways converge on the mitochondria to release cytochrome c into the cytosol where it binds to a proapoptotic regulator, Apaf1. The cytochrome c/Apaf1 complex recruits and activates the cysteine protease caspase 9 to form an active proteolytic complex known as the apoptosome. Although BCR-Abl has been shown to exert its anti-apoptotic effects by preventing cytochrome c release, addition of purified BCR-Abl to an in vitro apoptosis system inhibited caspase activity after mitochondrial release of cytochrome c. Furthermore, caspase activity was inhibited when cytochrome c was added to lysates from BCR-Abl-expressing mammalian cells. Therefore, it is hypothesized that BCR-Abl directly modulates the apoptosome to inhibit apoptosis. The goal of this proposal is to elucidate the mechanism by which BCR-Abl inhibits the apoptosome to block cell death. The results from this study will reveal new apoptotic regulators that can eventually be targeted to sensitize resistant cells to chemotherapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32GM069227-03
Application #
7029477
Study Section
Special Emphasis Panel (ZRG1-F05 (20))
Program Officer
Portnoy, Matthew
Project Start
2003-08-01
Project End
2006-07-31
Budget Start
2005-03-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2004
Total Cost
$18,962
Indirect Cost
Name
University of Vermont & St Agric College
Department
Pathology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405