HORMONAL CONTROL OF PROLIFERATION MALIGNANT THYMOCYTES

糖皮质激素抑制淋巴细胞增殖 胸腺起源 这一过程与胸腺退化有关 在正常的胸腺发育过程中。 恶性T淋巴瘤和 白血病细胞也受到糖皮质激素的生长抑制， 并且这种类固醇广泛用于化疗， 淋巴组织增生性疾病 理性地对待 糖皮质激素的化疗作用要求我们 了解这些激素调节淋巴细胞的机制 细胞增殖 我们的工作假设是， 不同的机制占主导地位。 一种是细胞溶解， 可归因于核酸酶的诱导或激活， 降解细胞核DNA 已经分离出变异体， 在体内对糖皮质激素的细胞溶解作用具有抗性。这些 表达功能齐全的受体。 有人建议，这些是 糖皮质激素介导的DNA降解或修复的变体。 到 为了验证这一假设，将进行实验来估计 野生型P1798中DNA损伤和修复的相对速率 细胞和那些不表达溶细胞因子的变体 表型 糖皮质激素也能抑制P1798细胞的增殖 在没有细胞溶解反应的情况下。 这表明 细胞溶解和增殖抑制是不同的现象。 有人提出，抑制增殖是由于 抑制某些基因的表达，这些基因对 通过细胞周期的进展。 糖皮质激素抑制 对基因表达知之甚少。 一系列的实验是 研究抑制机制。 主要重点 将是了解编码胸苷的基因的调节 激酶（TK）。 TK受到以下物质的继发性抑制： 转录。 将进行实验以测试 假设这是由于激素调节的因素， 是TK转录所必需的。 一系列平行的 将进行实验以研究 糖皮质激素抑制P1798细胞c-myc基因转录。

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.