HORMONAL CONTROL OF MALIGNANT THYMOCYTE PROLIFERATION

糖皮质激素抑制小鼠淋巴样细胞增殖 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 白血病细胞也会被糖皮质激素抑制生长， 而这类类固醇被广泛用于癌症的化疗。 淋巴增生性疾病。以理性的方式对待 糖皮质激素的化疗效果要求我们 了解这些激素调节淋巴系统的机制 细胞增殖。我们的工作假说是两个 不同的机制占了上风。一种是细胞溶解，它似乎 可归因于诱导或激活核酸酶 降解核DNA。已经分离出的变种是 在体内抵抗糖皮质激素的细胞溶解作用。这些 表达功能齐全的受体。据建议，这些都是 糖皮质激素介导的DNA降解或修复的变体。至 检验这一假设，将进行实验以估计 野生型P1798 DNA损伤与修复的相对速率 细胞和那些不表达细胞溶解的变异体 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， 细胞溶解和抑制增殖是不同的现象。 有人提出，抑制扩散是由于 抑制某些基因的表达，这些基因对 在细胞周期中进行。糖皮质激素抑制作用的研究 人们对基因的表达知之甚少。一系列的实验是 建议对其抑制机制进行研究。重点放在 将是了解编码胸苷的基因的调控 激酶(TK)。TK受到次级抑制 抄写。将进行实验，以测试 假设这是由于激素调节的因素， 是转录TK所必需的。平行的一系列 将进行实验以研究其作用机理 糖皮质激素抑制P1798细胞c-myc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.