University of California, Berkeley
1991 Searle Scholar
We are interested in molecular biology of programmed cell death and cell cycle control, T lymphocyte development and regulation of T-cell receptor gene rearrangement and expression. We are using mouse and human cell lines as well as transgenic and knock-out mice to study these processes.
Cell cycle control in apoptosis. In addition to apoptosis, anti-TCR signals in T cell hybridomas also lead to G1 arrest. How G1 arrest is linked to apoptosis is an interesting question. We have recently isolated a novel p19 cell cycle inhibitor, based on its ability to associate with Nur77 in a yeast 2 hybrid system. p19 consists of 4 ankyrin repeats and is homologous to the p16ink4 tumor suppressor gene. p19 associates with the G1 cyclin dependent kinase cdk4/cdk6 in vitro and in vivo but not with other cdk proteins or the cyclins. Overexpression of p19 leads to inhibition of the cyclinD/cdk4 kinase activity. Further biochemical and genetic experiments are aimed at understanding mechanisms of cell cycle regulation by p19 and the relationship between cell cycle arrest and apoptosis.
Regulation of rearrangement and expression of T-cell antigen receptor genes (TCR). Based on T cell receptor surface expression and function, T cells can be divided into 2 separate lineages (alpha-beta and gamma-delta T cells). TCR is a heterodimeric protein composed of either alpha-beta or gamma-delta subunits with which T cells can recognize foreign antigen. Each of the genes encoding all four TCR is comprised of several gene segments (V:variable, J:joining, C:constant) which rearrange during development. The process of V(D)J rearrangement is developmentally and tissue-sepcifically regulated. Studies using transgenic mice and cell lines suggest that chromatin accessibility plays a crucial role in this process. The TCR alpha-delta locus is particularly interesting as the delta is located within the alpha gene segments. Differential chromatin accessibility must occur to account for the differential developmental activation of the alpha and delta TCR genes. We have found 8 DNase I hypersensitive sites at 3' of the T cell receptor alpha-delta locus, which contain an LCR activity in transgenic mice. We put forward an LCR competition model to explain the differential accessibility of the alpha versus delta region during T cell development. In this model, the relative gene order to LCR plays an important role in regulation of chromatin structure. Current experiments using knock-out and transgenic mice are underway to test this model.
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