This proposal is based on the theory that the Bcl-2 proto-oncogene has both an anti-apoptotic activity, as well as the proliferation restraining activity. The investigator proposes to test the hypothesis that gain of function mutants of Bcl-2 can lead to enhanced oncogenesis and resistance to chemotherapeutic drugs. Transformation-enhancing mutants of Bcl-2 will be identified by somatic mutations in human tumors, as well as isolated from a random in vitro generated mutant library. The mutants will be transduced into primary bone marrow cells from transgenic mice which over-express the c-Myc oncogene using retroviral vectors. Mutants will be identified by in vitro colony forming assays on soft agar and in vivo by tumor formation in transplanted normal non-transgenic mice. Mutants of Bcl-2 which confer enhanced resistance to apoptosis induced by anti-cancer drugs will also be isolated from naturally drug-resistant human tumor cells. The anti-apoptosis activity, the effect on cell cycle regulation and the ability to form complexes with known cellular proteins and other various mutants will be studied. The long term objective of these specific aims is to design effective anti-Bcl-2 strategies. The final specific aim will investigate the role of the pro-apoptotic gene BIK in inducing apoptosis in tumor cells such as human prostate carcinoma cells which over-express Bcl-2. These studies hope to provide tools and strategies to interfere with Bcl-2 activity in neoplastic diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA073803-01A1
Application #
2470710
Study Section
Pathology B Study Section (PTHB)
Program Officer
Spalholz, Barbara A
Project Start
1997-12-05
Project End
2002-11-30
Budget Start
1997-12-05
Budget End
1998-11-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Vijayalingam, S; Pillai, Sreeraj G; Rashmi, Ramachandran et al. (2010) Overexpression of BH3-Only Protein BNIP3 Leads to Enhanced Tumor Growth. Genes Cancer 1:964-71
Lomonosova, Elena; Ryerse, Jan; Chinnadurai, G (2009) BAX/BAK-independent mitoptosis during cell death induced by proteasome inhibition? Mol Cancer Res 7:1268-84
Chinnadurai, G; Vijayalingam, S; Rashmi, R (2008) BIK, the founding member of the BH3-only family proteins: mechanisms of cell death and role in cancer and pathogenic processes. Oncogene 27 Suppl 1:S20-9
Rashmi, R; Pillai, S G; Vijayalingam, S et al. (2008) BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 27:1366-75
Chinnadurai, G; Vijayalingam, S; Gibson, S B (2008) BNIP3 subfamily BH3-only proteins: mitochondrial stress sensors in normal and pathological functions. Oncogene 27 Suppl 1:S114-27
Lomonosova, E; Chinnadurai, G (2008) BH3-only proteins in apoptosis and beyond: an overview. Oncogene 27 Suppl 1:S2-19
Subramanian, T; Vijayalingam, S; Lomonosova, Elena et al. (2007) Evidence for involvement of BH3-only proapoptotic members in adenovirus-induced apoptosis. J Virol 81:10486-95
Subramanian, T; Chinnadurai, G (2003) Pro-apoptotic activity of transiently expressed BCL-2 occurs independent of BAX and BAK. J Cell Biochem 89:1102-14
Lomonosova, Elena; Subramanian, T; Chinnadurai, G (2002) Requirement of BAX for efficient adenovirus-induced apoptosis. J Virol 76:11283-90
Theodorakis, Paul; Lomonosova, Elena; Chinnadurai, G (2002) Critical requirement of BAX for manifestation of apoptosis induced by multiple stimuli in human epithelial cancer cells. Cancer Res 62:3373-6

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