SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

信号转导事件和细胞生长的调节

• 批准号: 3774615
• 负责人: J B TREPEL
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774615
• 关键词: G protein; biological signal transduction; cell growth regulation; clone cells; fatty acylation; gene expression; growth inhibitors; hormone related neoplasm /cancer; human tissue; lovastatin; molecular oncology; myristates; neoplastic cell; neoplastic growth; neoplastic transformation; oncogenes; oncoproteins; oxidoreductase inhibitor; prostate neoplasms; transforming growth factors; tumor suppressor genes

This project is designed to increase our understanding of the biology of prostate cancer and to develop a new approach to the treatment of advanced prostatic cancer through the study of the signal transduction events regulating the growth of human prostate carcinoma cell lines. This work is currently focused on (1)the anticancer activity of HMG-CoA reductase inhibitor lovastatin, and (2)the role of heterotrimeric G proteins in malignant transformation and the molecular mechanisms regulating G protein expression. We have found that lovastatin treatment markedly alters the subcellular distribution of critical growth-regulatory gene products, including c-myc and the retinoblastoma protein, and that this redistribution is associated with shifts in the balance of protein phosphorylation and O-linked glycosylation. The data suggest that drugs of this class may be used to interrupt nuclear oncoprotein function, Studies of the G protein phenotype of prostate cancer cells showed that hormone-refractory cells express abundant membrane-associated G alpha 12, alpha l3, alpha il,2, and alphaz, in marked contrast to hormone-sensitive cells that have no detectable membrane-associated protein. This is particularly important in light of recent studies implicating G alpha subunits in malignant transformation. Hormone-sensitive cells were found to transcribe and translate alpha subunits but not insert them in the plasma membrane. Protein myristoylation is believed to be important in the tethering of signalling molecules including G alpha subunits and src to the plasma membrane. We found that hormone-sensitive cells had almost undetectable levels of the message encoding N-myristoyltransferase, the enzyme that catalyzes protein N-myristoylation, and that total cellular myristoylation was almost undetectable, in contrast to the androgen- independent cells in which both mRNA for the acylating enzyme and total cellular myristoylated protein were readily detectable.

这个项目旨在增加我们对生物学的理解， 前列腺癌和开发一种新的方法来治疗晚期 通过研究前列腺癌的信号转导事件 调节人前列腺癌细胞系的生长。 这项工作 HMG-CoA还原酶的抗癌活性 抑制剂洛伐他汀，和（2）异源三聚体G蛋白的作用， 恶性转化与G蛋白调控的分子机制 表情 我们发现，洛伐他汀治疗显著改变了 关键生长调节基因产物的亚细胞分布， 包括c-myc和视网膜母细胞瘤蛋白， 再分配与蛋白质平衡的变化有关 磷酸化和O-连接的糖基化。 数据显示，药物 可用于中断核癌蛋白功能， 对前列腺癌细胞G蛋白表型的研究表明， 难治性细胞表达丰富的膜相关G α 12， α l3，α il，2和α z，与对葡萄糖敏感的 没有可检测的膜相关蛋白的细胞。 这是 特别重要的是，鉴于最近的研究表明，G α 恶性转化中的亚基。 发现了激素敏感细胞 转录和翻译α亚基，但不将它们插入到 质膜 蛋白质豆蔻酰化被认为是重要的 包括G α亚基和src在内的信号分子的束缚 到细胞膜上。 我们发现，敏感细胞几乎 不可检测水平的信息编码N-肉豆蔻酰转移酶， 催化蛋白质N-豆蔻酰化的酶， 肉豆蔻酰化几乎检测不到，与雄激素相反， 独立的细胞，其中既有mRNA的酰化酶和总 细胞豆蔻酰化蛋白易于检测。