MNK1 pathway activity maintains protein synthesis in rapalog-treated gliomas
Michal Grzmil,Roland M. Huber,Daniel Hess,Stephan Frank,Debby Hynx,Gerald Moncayo,Dominique Klein,Adrian Merlo,Brian A. Hemmings +8 more
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TLDR
Combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model, indicating a molecular cross-talk between the m TORC1 andMNK1 pathways that has potential to be exploited therapeutically.Abstract:
High levels of mammalian target of rapamycin complex 1 (mTORC1) activity in malignant gliomas promote tumor progression, suggesting that targeting mTORC1 has potential as a therapeutic strategy. Remarkably, clinical trials in patients with glioma revealed that rapamycin analogs (rapalogs) have limited efficacy, indicating activation of resistance mechanisms. Targeted depletion of MAPK-interacting Ser/Thr kinase 1 (MNK1) sensitizes glioma cells to the mTORC1 inhibitor rapamycin through an indistinct mechanism. Here, we analyzed how MNK1 and mTORC1 signaling pathways regulate the assembly of translation initiation complexes, using the cap analog m7GTP to enrich for initiation complexes in glioma cells followed by mass spectrometry-based quantitative proteomics. Association of eukaryotic translation initiation factor 4E (eIF4E) with eIF4E-binding protein 1 (4EBP1) was regulated by the mTORC1 pathway, whereas pharmacological blocking of MNK activity by CGP57380 or MNK1 knockdown, along with mTORC1 inhibition by RAD001, increased 4EBP1 binding to eIF4E. Furthermore, combined MNK1 and mTORC1 inhibition profoundly inhibited 4EBP1 phosphorylation at Ser65, protein synthesis and proliferation in glioma cells, and reduced tumor growth in an orthotopic glioblastoma (GBM) mouse model. Immunohistochemical analysis of GBM samples revealed increased 4EBP1 phosphorylation. Taken together, our data indicate that rapalog-activated MNK1 signaling promotes glioma growth through regulation of 4EBP1 and indicate a molecular cross-talk between the mTORC1 and MNK1 pathways that has potential to be exploited therapeutically.read more
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Mnks, eIF4E phosphorylation and cancer.
TL;DR: The Mnks and/or the phosphorylation of eIF4E have been suggested to regulate the expression of proteins involved in cell cycle progression, cell survival and cell motility, and the utility of targeting the Mnks in cancer therapy is evaluated.
Journal ArticleDOI
NDR functions as a physiological YAP1 kinase in the intestinal epithelium.
Lei Zhang,Fengyuan Tang,Luigi Terracciano,Debby Hynx,Reto S. Kohler,Sandrine Bichet,Daniel Hess,Peter Cron,Brian A. Hemmings,Alexander Hergovich,Debora Schmitz-Rohmer +10 more
TL;DR: Mammalian NDR1/2 is established as bona fide kinases that target YAP1 on S127 in vitro and in vivo and has important implications for a broad range of research efforts aimed at decoding and eventually manipulating Yap1 biology in cancer settings, regenerative medicine, and possibly also noncancer human diseases.
Journal ArticleDOI
Tuning Specific Translation in Cancer Metastasis and Synaptic Memory: Control at the MNK–eIF4E Axis
TL;DR: The studies suggest that MNKs control the translation of specific mRNAs in cancer metastasis and neuronal synaptic plasticity by a novel mechanism involving the regulation of the translational repressor, cytoplasmic fragile-X protein-interacting protein 1 (CYFIP1).
Journal ArticleDOI
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 J. Peroutka,Krystyna Mazan-Mamczarz,James J. Steinhardt,Anup Mahurkar,Kevin G. Becker,Katherine L. B. Borden,Ronald B. Gartenhaus +14 more
TL;DR: It is proposed that MNKs can modulate oncogenic translation by regulating eif4E1-eIF4E3 levels and activity in DLBCL and exhibits a unique translatome that unveils a novel role for eIF 4E3 in translation initiation.
References
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TL;DR: The interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated gliobeasts, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
Book
WHO classification of tumours of the central nervous system
TL;DR: The current edition of the WHO Classification of Tumours of the Central Nervous System will serve as an indispensable textbook for all of those involved in the diagnosis and management of patients with tumors of the CNS, and will make a valuable addition to libraries in pathology, radiology, oncology, and neurosurgery departments.
Journal ArticleDOI
Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets
TL;DR: Recent advances in understanding of the molecular structures and biochemical functions of the translation initiation machinery are described and key strategies that mediate general or gene-specific translational control are summarized, particularly in mammalian systems.