Hirsch S, Miskimins R, Miskimins W K
University of South Dakota School of Medicine, Department of Biochemistry and Molecular Biology, Vermillion 57069, USA.
Recept Signal Transduct. 1996;6(3-4):121-9.
Transferrin receptor gene expression is coupled to cell proliferation of normal cells and is elevated in nearly all types of tumor cells. A mitogen-responsive region of the transferrin receptor gene promoter has been localized between -78 and -34 relative to the major transcriptional start. The promoter can be activated in quiescent fibroblasts by treatment with either vanadate or phenylarsine oxide, both of which are inhibitors of tyrosine phosphatases and lead to elevated levels of intracellular tyrosine-phosphorylated proteins. Vanadate can act synergistically with other mitogens and, when added together with serum, leads to superactivation of the promoter. Genistein, an inhibitor of certain tyrosine kinases, actually enhances promoter activity in cells treated with either vanadate or phenylarsine oxide. On the other hand, geldanamycin, which also reduces the level of tyrosine-phosphorylated proteins and promoters the morphological reversion of many transformed cell types, is a potent inhibitor of transferrin receptor promoter activation by mitogens. The differential effects of these two tyrosine kinase inhibitors is most likely caused by the specificity of the enzymes that they target. These results indicate that a tyrosine phosphorylation event plays a critical role in the signaling events that lead to activation of the transferrin receptor gene promoter in mitogen-stimulated cells. This is of interest because activation of this promoter is a delayed response that occurs several hours after mitogen addition.
转铁蛋白受体基因的表达与正常细胞的增殖相关联，并且在几乎所有类型的肿瘤细胞中都有所升高。转铁蛋白受体基因启动子的有丝分裂原反应区域已定位在相对于主要转录起始点的-78至-34之间。通过用钒酸盐或苯砷氧化物处理，可以在静止的成纤维细胞中激活该启动子，这两种物质都是酪氨酸磷酸酶的抑制剂，并导致细胞内酪氨酸磷酸化蛋白水平升高。钒酸盐可以与其他有丝分裂原协同作用，当与血清一起添加时，会导致启动子的超激活。染料木黄酮是某些酪氨酸激酶的抑制剂，实际上会增强用钒酸盐或苯砷氧化物处理的细胞中的启动子活性。另一方面，格尔德霉素也会降低酪氨酸磷酸化蛋白的水平并促进许多转化细胞类型的形态逆转，它是有丝分裂原激活转铁蛋白受体启动子的有效抑制剂。这两种酪氨酸激酶抑制剂的不同作用很可能是由它们所靶向的酶的特异性引起的。这些结果表明，酪氨酸磷酸化事件在有丝分裂原刺激的细胞中导致转铁蛋白受体基因启动子激活的信号传导事件中起关键作用。这很有趣，因为该启动子的激活是一种延迟反应，发生在添加有丝分裂原数小时后。
