Mitogenic activation of the transferrin receptor gene promoter is modulated by inhibitors of tyrosine kinases and tyrosine phosphatases.

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.