HORMONAL CONTROL OF PROLIFERATION MALIGNANT THYMOCYTES

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Glucocorticoid inhibit the proliferation of lymphoid cells of thymic origin. This process is involved in thymic involution during normal thymic development. Malignant T lymphoma and leukemia cells are also subject to growth arrest by glucocorticoid, and such steroids are widely used in chemotherapy of lymphoproliferative diseases. A rational approach to the chemotherapeutic effects of glucocorticoid requires that we understand the mechanisms whereby such hormones regulate lymphoid cell proliferation. Our working hypothesis states that two distinct mechanisms prevail. One is cytolysis, which appears to be attributable to induction or activation of nucleases that degrade the nuclear DNA. Variants have been isolated that are resistant to the cytolytic effects of glucocorticoid in vivo. These express fully functional receptors. It is proposed that these are variants in glucocorticoid-mediated DNA degradation or repair. To test this hypothesis, experiments will be carried out to estimate the relative rates of DNA damage and repair in wild type P1798 cells and those variants that do not express the cytolytic phenotype. Glucocorticoid can also inhibit the proliferation of P1798 cells in the absence of a cytolytic response. This indicates that cytolysis and inhibition of proliferation are distinct phenomena. It is proposed that inhibition of proliferation is due to inhibition of expression of certain genes that are critical for progression through the cell cycle. Glucocorticoid inhibition of gene expression is poorly understood. A series of experiments is proposed to study mechanisms of inhibition. The major emphasis will be to understand regulation of the gene encoding thymidine kinase (TK). TK is subject to secondary inhibition of transcription. Experiments will be carried out to test the hypothesis that this is due to hormonal regulation of factors that are required for transcription of TK. A parallel series of experiments will be carried out to study the mechanism whereby glucocorticoid inhibit transcription of c-myc in P1798 cells.