例如:"lncRNA", "apoptosis", "WRKY"

A MYC-GCN2-eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer.

Nat Cell Biol. 2019 Nov;21(11):1413-1424. Epub 2019 Nov 04
Stefanie Schmidt 1 , David Gay 2 , Friedrich Wilhelm Uthe 1 , Sarah Denk 1 , Madelon Paauwe 2 , Niels Matthes 1 , Markus Elmar Diefenbacher 3 , Sheila Bryson 2 , Fiona Clare Warrander 2 , Florian Erhard 4 , Carsten Patrick Ade 3 , Apoorva Baluapuri 3 , Susanne Walz 5 , Rene Jackstadt 2 , Catriona Ford 2 , Georgios Vlachogiannis 6 , Nicola Valeri 7 , Christoph Otto 1 , Christina Schülein-Völk 3 , Katja Maurus 8 , Werner Schmitz 3 , John Raymond Philip Knight 2 , Elmar Wolf 3 , Douglas Strathdee 2 , Almut Schulze 8 , Christoph-Thomas Germer 8 , Andreas Rosenwald 8 , Owen James Sansom 9 , Martin Eilers 10 , Armin Wiegering 11
Stefanie Schmidt 1 , David Gay 2 , Friedrich Wilhelm Uthe 1 , Sarah Denk 1 , Madelon Paauwe 2 , Niels Matthes 1 , Markus Elmar Diefenbacher 3 , Sheila Bryson 2 , Fiona Clare Warrander 2 , Florian Erhard 4 , Carsten Patrick Ade 3 , Apoorva Baluapuri 3 , Susanne Walz 5 , Rene Jackstadt 2 , Catriona Ford 2 , Georgios Vlachogiannis 6 , Nicola Valeri 7 , Christoph Otto 1 , Christina Schülein-Völk 3 , Katja Maurus 8 , Werner Schmitz 3 , John Raymond Philip Knight 2 , Elmar Wolf 3 , Douglas Strathdee 2 , Almut Schulze 8 , Christoph-Thomas Germer 8 , Andreas Rosenwald 8 , Owen James Sansom 9 , Martin Eilers 10 , Armin Wiegering 11
+ et al

[No authors listed]

Author information
  • 1 Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Würzburg, Würzburg, Germany.
  • 2 CRUK Beatson Institute, Glasgow, UK.
  • 3 Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany.
  • 4 Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
  • 5 Comprehensive Cancer Center Mainfranken, Core Unit Bioinformatics, Biocenter, University of Würzburg, Am Hubland, Würzburg, Germany.
  • 6 Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
  • 7 Department of Medicine, The Royal Marsden NHS Trust, London, UK.
  • 8 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
  • 9 Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
  • 10 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. martin.eilers@biozentrum.uni-wuerzburg.de.
  • 11 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany. wiegering_a@ukw.de.

摘要


Tumours depend on altered rates of protein synthesis for growth and survival, which suggests that mechanisms controlling mRNA translation may be exploitable for therapy. Here, we show that loss of APC, which occurs almost universally in colorectal tumours, strongly enhances the dependence on the translation initiation factor eIF2B5. Depletion of eIF2B5 induces an integrated stress response and enhances translation of MYC via an internal ribosomal entry site. This perturbs cellular amino acid and nucleotide pools, strains energy resources and causes MYC-dependent apoptosis. eIF2B5 limits MYC expression and prevents apoptosis in APC-deficient murine and patient-derived organoids and in APC-deficient murine intestinal epithelia in vivo. Conversely, the high MYC levels present in APC-deficient cells induce phosphorylation of eIF2α via the kinases GCN2 and PKR. Pharmacological inhibition of GCN2 phenocopies eIF2B5 depletion and has therapeutic efficacy in tumour organoids, which demonstrates that a negative MYC-eIF2α feedback loop constitutes a targetable vulnerability of colorectal tumours.