Signaling by Tumor Necrosis Factor Family Members
2000 new Scholar Award in aging
The majority of patients with cancer in the United States are more than 70 years old and cancer has been regarded as a disease of aging. Aging-related decline of the immune response has also been well documented. Our long-term goals are to identify molecular targets for drug development against cancer and immunological diseases.
Tumor necrosis factor (TNF) family members play important roles in various physiological and pathological processes, including cell proliferation, differentiation, apoptosis and modulation of immune responses. TNF is the prototypic member of the TNF family. During the past several years, we have been working on the signaling pathways leading to the two major TNF-induced effects, apoptosis and activation of the anti-apoptotic and proinflammatory transcription factor NF-kB.
TRAIL is a recently identified protein that is homologous to TNF. Unlike TNF, TRAIL is capable of inducing apoptosis of various cancer cells, including some TNF-resistant cancer cells, but not of normal cells. In vivo experiments indicated that TRAIL was not toxic to animals. These early studies point to the possibility of developing TRAIL as a drug for cancer treatment. Although TRAIL has great promise on this aspect, some cancer cells are resistant to TRAIL treatment. The resistance of even a small fraction of cancer cells to TRAIL may limit its therapeutic potential because these resistant cancer cells can eventually grow into tumors. In the next four years, we will identify and clone the genes that are responsible for resistance to TRAIL treatment. Once identified and cloned, these genes can be used as targets for small molecule drug development. Suppression of the function and/or expression of these genes by small molecule drugs should enable TRAIL to kill all cancer cells, including those that are originally resistant to TRAIL.
Another project in our laboratory is to investigate the molecular mechanisms of TALL-1 signaling. TALL-1 is a new member of the TNF family that stimulates B lymphocyte proliferation and over-production of TALL-1 causes autoimmune diseases in animals. Recently, we have further identified that BCMA is a receptor for TALL-1. In the next couple of years, we will investigate the molecular mechanisms of TALL-1/BCMA signaling and clone genes involved in TALL-1 action. The genes and their protein products identified in these studies can be used as molecular targets for drug development against certain immuno-deficient and autoimmune diseases.