We have studied the activation of human peripheral blood T cells from a molecular perspective. Previously we have constructed a subtractive cDNA library and used subtractive and differential screening to isolate genes which are induced early on in T cells stimulated by mitogens. Such genes are likely to include new lymphokines and receptors as well as genes which control proliferation and thus may have oncogenic potential. So far, we have isolated more than 53 individual genes induced by mitogens in T cells and these include such genes as the c-myc oncogene and the interleukin-2 (IL-2) receptor gene. Also, we have studied the regulation of these genes. They can be grouped by their kinetics of induction, by their behavior in the presence of cycloheximide, by their sensitivity to cyclosporin A (an immunosuppressive drug) and by their inducibility with various distinct mitogens or activators (T cell receptor antibodies, IL-2, calcium ionophores, 13-phorbol-12-myristate acetate alone, phytohemagglutinin alone). Furthermore, some of these genes appear to be T cell specific, whereas others are inducible also in human fibroblasts. Lastly, we have discovered that some of these genes are activated by the human T lymphotropic virus I. We are now studying the effect of the tat I transactivating protein of this virus as well as the effect of the human immunodeficiency virus and its tat III protein on the activation mechanism in T cells. In addition to these studies, we have continued our efforts to understand the molecular mechanisms leading to the activation of the IL-2 gene in T cells, as well as the events leading to downregulation of c- myc during differentiation of HL60 and U937 cells. We have successfully transfected these latter cells with a c-myc promoter construct which can be regulated. Therefore, we have a model system in hand to understand the molecular elements required for this downregulation. Lastly, we have initiated new approaches to clone the high molecular weight B cell growth factor discovered in the LIR and characterized in other project reports.
| Leonardi, A; Chariot, A; Claudio, E et al. (2000) CIKS, a connection to Ikappa B kinase and stress-activated protein kinase. Proc Natl Acad Sci U S A 97:10494-9 |
| Ellinger-Ziegelbauer, H; Kelly, K; Siebenlist, U (1999) Cell cycle arrest and reversion of Ras-induced transformation by a conditionally activated form of mitogen-activated protein kinase kinase kinase 3. Mol Cell Biol 19:3857-68 |
