REGULATION OF TRANSFERRIN RECEPTOR MESSENGER-RNA EXPRESSION - DISTINCT REGULATORY FEATURES IN ERYTHROID-CELLS

In proliferating non-erythroid cells, the expression of transferrin re ceptors (TfR) is negatively regulated by the amount of intracellular i ron. Fe-dependent regulation of TfR occurs post-transcriptionally and is mediated by iron-responsive elements (IRE) located in the 3' untran slated region of the TfR mRNA. IREs are recognized by a specific cytop lasmic binding protein (IRE-BP) that, in the absence of Fe, binds with high affinity to TW mRNA, preventing its degradation. While TfR numbe rs are positively correlated with proliferation in non-erythroid cells , in hemoglobin-synthesizing cells, their numbers increase during diff erentiation and are, therefore, negatively correlated with proliferati on. This suggests a distinct regulation of erythroid TW expression and evidence, as follows, for this was found in the present study. (a) Wi th nuclear run-on assays, our experiments show increased TfR mRNA tran scription following induction of erythroid differentiation of murine e rythroleukemia (MEL) with Me(2)SO. (b) Me(2)SO treatment of MEL cells does not increase IRE-BP activity which is, however, increased in unin duced MEL cells by Fe chelators. (c) Following induction of MEL cells, there is an increase in the stability of TfR mRNA, whose level is onl y slightly affected by iron excess. (d) Heme-synthesis inhibitors, suc h as succinylacetone and isonicotinic acid hydrazide, which inhibit nu merous aspects of erythroid differentiation, also inhibit TfR mRNA exp ression in induced MEL cells. However, heme-synthesis inhibition does not lead to a decrease in TfR mRNA levels in uninduced MEL cells. Thus , these studies indicate that TfR gene expression is regulated differe ntly in hemoglobin synthesizing as compared to uninduced MEL cells.