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

Author

Listed:
  • Ari L. Landon

    (Marlene & Stewart Greenebaum Cancer Center, University of Maryland)

  • Parameswary A. Muniandy

    (Marlene & Stewart Greenebaum Cancer Center, University of Maryland
    Veterans Administration Medical Center)

  • 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
    Veterans Administration Medical Center)

  • 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
    Veterans Administration Medical Center)

  • 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
    Veterans Administration Medical Center)

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.

Suggested Citation

  • 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 & , 2014. "MNKs act as a regulatory switch for eIF4E1 and eIF4E3 driven mRNA translation in DLBCL," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6413
    DOI: 10.1038/ncomms6413
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