MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL

Ari L. Landon, Parameswary A. Muniandy, Amol C. Shetty, Elin Lehrmann, Laurent Volpon, Simone Houng, Yongqing Zhang, Bojie Dai, Raymond Peroutka, Krystyna Mazan-Mamczarz, James Steinhardt, Anup Mahurkar, Kevin G. Becker, Katherine L. Borden and Ronald B. Gartenhaus ()
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Ari L. Landon: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Parameswary A. Muniandy: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Amol C. Shetty: Institute for Genome Sciences, University of Maryland School of Medicine
Elin Lehrmann: Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health
Laurent Volpon: Institute for Research in Immunology and Cancer, Université de Montréal
Simone Houng: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Yongqing Zhang: Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health
Bojie Dai: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Raymond Peroutka: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Krystyna Mazan-Mamczarz: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
James Steinhardt: Marlene & Stewart Greenebaum Cancer Center, University of Maryland
Anup Mahurkar: Institute for Genome Sciences, University of Maryland School of Medicine
Kevin G. Becker: Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health
Katherine L. Borden: Institute for Research in Immunology and Cancer, Université de Montréal
Ronald B. Gartenhaus: Marlene & Stewart Greenebaum Cancer Center, University of Maryland

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract The phosphorylation of eIF4E1 at serine 209 by MNK1 or MNK2 has been shown to initiate oncogenic mRNA translation, a process that favours cancer development and maintenance. Here, we interrogate the MNK-eIF4E axis in diffuse large B-cell lymphoma (DLBCL) and show a distinct distribution of MNK1 and MNK2 in germinal centre B-cell (GCB) and activated B-cell (ABC) DLBCL. Despite displaying a differential distribution in GCB and ABC, both MNKs functionally complement each other to sustain cell survival. MNK inhibition ablates eIF4E1 phosphorylation and concurrently enhances eIF4E3 expression. Loss of MNK protein itself downregulates total eIF4E1 protein level by reducing eIF4E1 mRNA polysomal loading without affecting total mRNA level or stability. Enhanced eIF4E3 expression marginally suppresses eIF4E1-driven translation but exhibits a unique translatome that unveils a novel role for eIF4E3 in translation initiation. We propose that MNKs can modulate oncogenic translation by regulating eIF4E1-eIF4E3 levels and activity in DLBCL.

Date: 2014
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DOI: 10.1038/ncomms6413

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