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J. Biol. Chem., Vol. 283, Issue 26, 18461-18472, June 27, 2008

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mRNA Silencing in Human Erythroid Cell Maturation

HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN K CONTROLS THE EXPRESSION OF ITS REGULATOR c-Src^*

Isabel S. Naarmann, Christiane Harnisch, Nadine Flach, Elisabeth Kremmer, Hartmut Kühn^¶, Dirk H. Ostareck¹, and Antje Ostareck-Lederer²

From the Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Strasse 3, Halle (Saale) 06120, the Institute of Molecular Immunology, Helmholtz Center Munich, German Research Center for Environmental Health, Munich 81377, and the ^¶Institute of Biochemistry, Charité University Medicine Berlin, Berlin 10117, Germany

Erythroid precursor cells undergo nuclear extrusion and degradation of mitochondria when they mature to erythrocytes. It has been suggested before that the reticulocyte 15-lipoxygenase (r15-LOX) plays an important role in initiating the breakdown of mitochondria in rabbit reticulocytes. The expression of rabbit r15-LOX is regulated by the heterogeneous nuclear ribonucleoproteins (hnRNP) K and E1 at the translational level. However, this mechanism has never been confirmed in human erythropoiesis. Based on K562 cells we have set up an inducible human erythroid cell system. We show that, during induction, K562 cells exhibit changes in morphology and protein expression that are characteristic for terminal erythroid maturation: nuclear exclusion, expression of endogenous human r15-LOX regulated by hnRNP K and hnRNP E1, and loss of mitochondria. Importantly, induction of terminal erythroid maturation in primary human CD34⁺ cells recapitulated the results obtained in K562 cells. Employing the physiologically relevant K562 cell system we uncovered a new mechanism of interdependent post-transcriptional regulation of gene expression. The timely expression of the tyrosine kinase c-Src, which phosphorylates hnRNP K in later stages, is controlled by hnRNP K in early stages of erythroid maturation. hnRNP K binds to the 3'-untranslated region of the c-Src mRNA and inhibits its translation by blocking 80 S ribosome formation. In premature erythroid cells, small interfering RNA-mediated knockdown of hnRNP K, but not of hnRNP E1, leads to the de-repression of c-Src synthesis.

Received for publication, December 19, 2007 , and in revised form, April 18, 2008.

^* This work was supported by a Heisenberg Fellowship of the Deutsche Forschungsgemeinschaft (DFG) (to A. O. L.), by the DFG (Grants OS290/2-2 and OS 290/3-1 to A. O. L. and OS 135/2-3, OS 290/3-1, and GRK 1026 to D. H. O.), and by the European Community (Grant FP6, LSHM-CT-2004-0050333 to H. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence may be addressed: Tel.: 49-345-552-4816; Fax: 49-345-552-7014; E-mail: dostareck{at}biochemtech.uni-halle.de.

² To whom correspondence may be addressed: Tel.: 49-345-552-4949; Fax: 49-345-552-7014; E-mail: aostareck{at}biochemtech.uni-halle.de.

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