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Molecular and Cellular Biology, August 2001, p. 5500-5511, Vol. 21, No. 16
Arthritis and Bone Metabolism, Novartis
Pharma AG, CH-4002 Basel, Switzerland
Received 15 February 2001/Returned for modification 22 March
2001/Accepted 24 May 2001
Eukaryotic initiation factor 4E (eIF4E) is a key component of the
translational machinery and an important modulator of cell growth and
proliferation. The activity of eIF4E is thought to be regulated by
interaction with inhibitory binding proteins (4E-BPs) and
phosphorylation by mitogen-activated protein (MAP) kinase-interacting kinase (MNK) on Ser209 in response to mitogens and cellular stress. Here we demonstrate that phosphorylation of eIF4E via MNK1 is mediated
via the activation of either the Erk or p38 pathway. We further show
that expression of active mutants of MNK1 and MNK2 in 293 cells
diminishes cap-dependent translation relative to cap-independent
translation in a transient reporter assay. The same effect on
cap-dependent translation was observed when MNK1 was activated by the
Erk or p38 pathway. In line with these findings, addition of
recombinant active MNK1 to rabbit reticulocyte lysate resulted in a
reduced protein synthesis in vitro, and overexpression of MNK2 caused a
decreased rate of protein synthesis in 293 cells. By using CGP 57380, a
novel low-molecular-weight kinase inhibitor of MNK1, we demonstrate
that eIF4E phosphorylation is not crucial to the formation of the
initiation complex, mitogen-stimulated increase in cap-dependent
translation, and cell proliferation. Our results imply that activation
of MNK by MAP kinase pathways does not constitute a positive regulatory
mechanism to cap-dependent translation. Instead, we propose that the
kinase activity of MNKs, eventually through phosphorylation of eIF4E,
may serve to limit cap-dependent translation under physiological conditions.
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.16.5500-5511.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Negative Regulation of Protein Translation by
Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2
*
Corresponding author. Mailing address: Novartis Pharma
AG, WSJ 386.927, CH-4002 Basel, Switzerland. Phone: 41-61-3244376. Fax:
41-61-3249457. E-mail:
hermann.gram{at}pharma.novartis.com.
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