The aim of this investigation is to study the role of NF- B/Rel proteins in cell survival. I intend to take advantage of recently generated mice deficient in NF-kB and IkB RelA subunit in protection death signals generated by members of the TNFR family and in protection from oncogene-induced apoptosis. 1) TNFalpha toxicity to NF-kB deficient cells. The basis for the inability of RelA-/-macrophages and fibroblasts to survive in the presence of the proinflammatory cytokine TNFalpha will be investigated. The regulation of putative anti-apoptotic genes in RelA-/- cells will be studies. The specific domains of RelA and the role of other NF-kB subunits such as p50 and c-Rel in protection from TNFalpha cytotoxicity will be investigated in RelA-/-, p50-/-RelA-/-, and c-Rel-/-RelA-/- cells. Tumor cell lines naturally sensitive to TNFalpha will be analyzed to determine if NF-kB is a primary determinant of protection from TNFalpha cytotoxicity. 2) Role of RelA in protection from Fas and TNFR2 cytotoxicity. The sensitivity of RelA-/-T lymphocytes to Fas and TNFR2 mediated cell death will be investigated. These studies will determine whether RelA functions in an anti-apoptotic or pro-apoptotic capacity within these cells. Ceramide generated following TNFalpha and Fas-ligand stimulation has been proposed to mediate their apoptotic affects. This will be directly tested by determining the sensitivity of RelA-/- cells to ceramide. 3) Expression of transforming oncogenes in RelA-/- fibroblasts. Studies will be carried out to determine the basis for decreased capability of oncogenic ras or src to transform RelA-/-3T3 cells. In particular, experiments will be carried out to determine if these oncogenes induce cell death in RelA-/-fibroblasts. RelA will be reintroduced in these cells to test if the in situ presence of this protein is required for transformation and/or preventing cell death.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074892-02
Application #
2712885
Study Section
Pathology B Study Section (PTHB)
Program Officer
Mccarthy, Susan A
Project Start
1997-08-15
Project End
2001-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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