HORMONAL CONTROL OF PROLIFERATION MALIGNANT THYMOCYTES

恶性胸腺细胞增殖的激素控制

• 批准号: 3481978
• 负责人: E. AUBREY THOMPSON
• 金额: $ 18.67万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3481978
• 关键词: DNA; DNA damage; DNA repair; autoradiography; cell growth regulation; cytolysis; gene expression; genetic promoter element; genetic transcription; genome; glucocorticoids; hormone receptor; hormone regulation /control mechanism; laboratory mouse; leukocyte activation /transformation; lymphosarcoma; neoplastic growth; oncogenes; thymidylate kinase; thymus neoplasms; tissue /cell culture

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.

糖皮质激素抑制 胸腺起源。 这个过程与胸腺涉及 在正常胸腺发育期间。 恶性T淋巴瘤和 白血病细胞也受到糖皮质激素的生长停滞， 这种类固醇广泛用于化学疗法 淋巴增生性疾病。 理性的方法 糖皮质激素的化学治疗作用要求我们 了解这种激素调节淋巴样的机制 细胞增殖。 我们的工作假设指出两个 独特的机制占上风。 一个是细胞解，似乎 归因于诱导或激活的核酸酶 降解核DNA。 已孤立的变体 对糖皮质激素在体内的胞溶作用的抗性。这些 表达功能齐全的受体。 有人提出这些是 糖皮质激素介导的DNA降解或修复中的变体。 到 检验此假设，将进行实验以进行估计 野生型P1798中DNA损伤和修复的相对速率 细胞和那些不表达细胞溶解的变体 表型。 糖皮质激素还可以抑制p1798细胞的增殖 在没有细胞溶解反应的情况下。 这表明 细胞解析和抑制增殖是不同的现象。 有人提出抑制增生是由于 抑制某些对某些至关重要的基因的表达 通过细胞周期的进展。 糖皮质激素的抑制 基因表达知之甚少。 一系列实验是 提议研究抑制的机制。 主要重点 将了解编码胸苷的基因的调节 激酶（TK）。 TK受到次要抑制 转录。 将进行实验以测试 假设这是由于对因素的激素调节引起的 TK转录需要。 平行系列 实验将进行研究以研究的机制 糖皮质激素抑制P1798细胞中C-MYC的转录。