Impaired ferritin mRNA translation in primary erythroid progenitors: Shiftto iron-dependent regulation by the nu-ErbA oncoprotein

In immortalized cells of the erythroid lineage, the iron-regulatory protein (IRP) has been suggested to coregulate biosynthesis of the iron storage pr otein ferritin and the erythroid delta-aminolevulinate synthase (eALAS), a key enzyme in heme production. Under iron scarcity, IRP binds to an iron-re sponsive element (IRE) located in ferritin and eALAS mRNA leaders, causing a block of translation. In contrast, IRP-IRE interaction is reduced under h igh iron conditions, allowing efficient translation. We show here that prim ary chicken erythroblasts (ebls) proliferating or differentiating in cultur e use a drastically different regulation of iron metabolism. Independently of iron administration, ferritin H (ferH) chain mRNA translation was massiv ely decreased, whereas eALAS transcripts remained constitutively associated with polyribosomes, indicating efficient translation. Variations in iron s upply had minor but significant effects on eALAS mRNA polysome recruitment but failed to modulate IRP-affinity to the ferH-IRE in vitro. However, leuk emic ebls transformed by the v-ErbA/v-ErbB-expressing avian erythroblastosi s virus showed an iron-dependent reduction of IRP mRNA-binding activity, re sulting in mobilization of ferH mRNA into polysomes. Hence, we analyzed a p anel of ebls overexpressing v-ErbA and/or v-ErbB oncoproteins as well as th e respective normal cellular homologues (c-ErbA/TR alpha, c-ErbB/EGFR). It turned out that v-ErbA, a mutated class II nuclear hormone receptor that ar rests erythroid differentiation, caused the change in ferH mRNA translation . Accordingly, inhibition of v-ErbA function in these leukemic ebls led to a switch from iron-responsive to iron-independent ferH expression. (C) 1999 by The American Society of Hematology.