SIGNAL TRANSDUCTION EVENTS AND THE REGULATION OF CELL GROWTH

这个项目是为了增加我们对生物的了解 为前列腺癌和晚期前列腺癌的治疗开辟新的途径 前列腺癌通过信号转导事件的研究 调节人前列腺癌细胞系的生长。这部作品 目前主要集中在(1)HMG-CoA还原酶的抗癌活性 抑制剂洛伐他汀，以及(2)异三聚体G蛋白在 恶性转化及其调控G蛋白的分子机制 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，而这 再分配与蛋白质平衡的变化有关。 磷酸化和O-连接糖基化。数据表明，药物 这类物质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 激素不耐受细胞表达丰富的膜相关Gα12， Alpha L3、Alpha IL、2和Alphaz，与激素敏感型形成鲜明对比 没有可检测到的膜相关蛋白的细胞。这是 尤其重要的是，鉴于最近的研究涉及Gα 恶变中的亚单位。发现了激素敏感细胞 转录和翻译阿尔法亚单位，但不将它们插入 质膜。蛋白质肉豆蔻酰化被认为在 包括Gα亚基和src在内的信号分子的连接 到质膜上。我们发现对激素敏感的细胞几乎 无法检测到编码N-肉豆蔻酰基转移酶的消息的水平， 催化蛋白质N-肉豆蔻酰化的酶，以及整个细胞 肉豆蔻酰化几乎检测不到，与雄激素相反- 在独立的细胞中，酰化酶的mRNA和总 细胞内肉豆蔻酰化蛋白很容易被检测到。

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.