Understanding the cellular responses to tumor necrosis factor (TNF) has remained an elusive goal. Although every nucleated cell type examined to date displays TNF-receptors (TNF-Rs), ligand binding does not predict biologic responsiveness. Upon isolating and cloning the genes for human TNF-Rs, it was clear that these ligand binding peptides lacked consensus sequences typical of known kinases or substrates for kinases, thereby strongly suggesting the co-association of accessory molecules for the formation of a biologically active TNF-R complex. Preliminary evidence has shown that the lymphocyte TNF-R can functionally associate with another cell surface protein. This protein, designated Fas, is predicted to function as a signal transduction molecule. In addition to its potential role in transmembrane signalling, Fas can regulate additional cellular processes leading to differential apoptotic cell death in activated lymphocytes. To date, little is known about the molecular nature and function. of Fas. The research plan proposed in this application is designed to explore such parameters. Specifically, this includes characterizing the molecular nature of the lymphocyte Fas molecule, comparing it to that of myeloid and hematopoietic tumor cell lines, determining its physical association with the TNF-R, and elucidating its role in transmembrane signalling. Tbe knowledge gained from these studies will extend our understanding of the obligate requirement for TNF in cytotoxic lymphocyte development and may provide the therapeutic basis for exploitation of Fas-triggered apoptotic cell death in autoimmune disease, graft rejection and/or malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA055195-04
Application #
2096401
Study Section
Experimental Immunology Study Section (EI)
Project Start
1991-08-01
Project End
1996-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Owen-Schaub, L B; Radinsky, R; Kruzel, E et al. (1994) Anti-Fas on nonhematopoietic tumors: levels of Fas/APO-1 and bcl-2 are not predictive of biological responsiveness. Cancer Res 54:1580-6
Owen-Schaub, L B; Meterissian, S; Ford, R J (1993) Fas/APO-1 expression and function on malignant cells of hematologic and nonhematologic origin. J Immunother Emphasis Tumor Immunol 14:234-41
Owen-Schaub, L B; Yonehara, S; Crump 3rd, W L et al. (1992) DNA fragmentation and cell death is selectively triggered in activated human lymphocytes by Fas antigen engagement. Cell Immunol 140:197-205