DFG Research Group FOR855

    Translational control of gene expression in maturing erythroid cells

    PD Dr. Antje Ostareck-Lederer
    PD Dr. Dirk H. Ostareck

    Project Summary:

    Early in maturation erythroid cells lose their capacity for mRNA synthesis due to the extrusion of the nucleus. Therefore, the stability and translation of mRNAs coding for specific proteins which function only in late stages of maturation must be controlled. We have studied the mechanism by which reticulocyte 15-Lipoxygenase (r15-LOX) mRNA expression is temporally restricted. This is achieved by a protein complex formed at the differentiation control element (DICE) in the 3’UTR. We identified hnRNP K and hnRNP E1 as components of the complex that inhibits mRNA translation by blocking 60S ribosomal subunit binding to the 40S subunit at the initiation codon. This might be achieved in two ways: Either hnRNP K and hnRNP E1 modulate the function of translation initiation factors directly or they might act via an as yet unidentified factor. To address this question we have established a human inducible erythroid cell system, which recapitulate DICE-dependent translational regulation in vitro and in vivo. The project focuses on the identification of additional factors involved in the silencing of r15-LOX mRNA. We also study the complex composition and/or post-translational modification(s) of individual factors in these complexes during erythroid cell maturation. Furthermore we investigate how the factors involved in translation regulation are degraded during erythroid cell maturation.

    Selected publications (2007-09):

    1.    Adolph, D., Flach, N., Müller, K., Ostareck, D.H. and Ostareck-Lederer, A.: Deciphering the crosstalk between hnRNP K and c-Src: The c-Src activation domain in hnRNP K is distinct from the site of interaction.
    (2007) Mol. Cell. Biol. 27, 1758-1770.

    2.    Isken, O., Baroth, M., Grassmann, C., Weinlich, S., Ostareck, D.H., Ostareck-Lederer, A. and Behrens, S.E.: Nuclear factors are involved in Hepatitis C Virus RNA replication.
    (2007) RNA 13, 1675-1692.

    3.    Naarmann, I., Harnisch, C., Flach, N., Kremmer, E., Kühn, H., Ostareck, D.H. and Ostareck-Lederer, A.: mRNA silencing in human erythroid cell maturation: hnRNP K controls the synthesis of its regulator c-Src.
    (2008) J. Biol. Chem., 283, 18461-18472.

    4.    Fronz, K., Otto, S., Kölbel, K., Kühn, U., Friedrich, H., Schierhorn, A., Beck-Sickinger, A., Ostareck-Lederer, A. and Elmar Wahle: Promiscuous modification of the nuclear poly(A) binding protein by multiple protein arginine methyl transferases does not affect the aggregation behaviour.
    (2008) J. Biol. Chem. 283, 20408-20420.

    5.    Weinlich, S., Hüttelmaier, S. Schierhorn, A., Behrens, S.E., Ostareck-Lederer, A. and Ostareck, D.H.: IGF2BP1 enhances HCV IRES-mediated translation initiation via the 3’UTR.
    (2009) RNA 15, 1528-1542.

    6.    Davison, E.J., Pennington, K., Hung, C.-C., Peng, J. Rafiq, R., Ostareck-Lederer, A., Ostareck, D.H., Ardley, H.C., Banks, R.E., Robinson, P.A.: Proteomic analysis of increased Parkin expression and its interactants provides evidence for a role in modulation of mitochondrial function.
    (2009) Proteomics 9, 4284-4297.