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Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4023-4030
RAPID COMMUNICATION
Thrombopoietin Production Is Inhibited by a Translational Mechanism
Nico Ghilardi,
Adrian Wiestner, and
Radek C. Skoda
From Biozentrum, University of Basel, Basel, Switzerland.
Thrombopoietin (TPO) is a lineage-dominant hematopoietic cytokine
that regulates megakaryopoiesis and platelet production. The major site
of TPO biosynthesis is the liver. Despite easily detectable levels of
liver TPO mRNA, the circulating TPO serum levels are very low. We have
observed that translation of TPO mRNA is inhibited by the presence of
inhibitory elements in the 5 -untranslated region (5-UTR).
Alternative promoter usage and differential splicing generate at least
three TPO mRNA isoforms that differ in the composition of their
5-UTR. Using mutational analysis we show that physiologically
the translation of these TPO mRNA isoforms is strongly inhibited by the
presence of AUG codons, which define several short open reading frames
(ORFs) in the 5-UTR and suppress efficient initiation at the
physiologic start site. The two regularly spliced isoforms, which
account for 98% of TPO mRNA, were almost completely inhibited, whereas a rare splice variant that lacks exon 2 can be more efficiently translated. Thus, inhibition of translation of the TPO mRNA is an
efficient mechanism to prevent overproduction of this highly potent
cytokine.
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