Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4321-4332
Impaired Ferritin mRNA Translation in Primary Erythroid
Progenitors: Shift to Iron-Dependent Regulation by the v-ErbA
Oncoprotein
Wolfgang Mikulits,
Matthias Schranzhofer,
Anton Bauer,
Helmut Dolznig,
Lioba Lobmayr,
Anthony A. Infante,
Hartmut Beug, and
Ernst
W. Müllner
From the Institute of Molecular Biology and Institute of Molecular
Pathology, Vienna Biocenter, University of Vienna, Vienna, Austria; and
the Department of Molecular Biology and Biochemistry, Wesleyan
University, Middletown, CT.
In immortalized cells of the erythroid lineage, the iron-regulatory
protein (IRP) has been suggested to coregulate biosynthesis of the iron
storage protein ferritin and the erythroid delta-aminolevulinate synthase (eALAS), a key enzyme in heme production. Under iron scarcity,
IRP binds to an iron-responsive element (IRE) located in ferritin and
eALAS mRNA leaders, causing a block of translation. In contrast,
IRP-IRE interaction is reduced under high iron conditions, allowing
efficient translation. We show here that primary chicken erythroblasts
(ebls) proliferating or differentiating in culture use a drastically
different regulation of iron metabolism. Independently of iron
administration, ferritin H (ferH) chain mRNA translation was massively
decreased, whereas eALAS transcripts remained constitutively associated
with polyribosomes, indicating efficient translation. Variations in
iron supply had minor but significant effects on eALAS mRNA polysome
recruitment but failed to modulate IRP-affinity to the ferH-IRE in
vitro. However, leukemic ebls transformed by the
v-ErbA/v-ErbB-expressing avian erythroblastosis virus showed an
iron-dependent reduction of IRP mRNA-binding activity, resulting in
mobilization of ferH mRNA into polysomes. Hence, we analyzed a panel of
ebls overexpressing v-ErbA and/or v-ErbB oncoproteins as well as the
respective normal cellular homologues (c-ErbA/TR
, c-ErbB/EGFR). It
turned out that v-ErbA, a mutated class II nuclear hormone receptor
that arrests 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.
