Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis Journal Article


Authors: Lin, C. J.; Nasr, Z.; Premsrirut, P. K.; Porco, J. A.; Hippo, Y.; Lowe, S. W.; Pelletier, J.
Article Title: Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis
Abstract: The energetically demanding process of translation is linked to multiple signaling events through mTOR-mediated regulation of eukaryotic initiation factor (eIF)4F complex assembly. Disrupting mTOR constraints on eIF4F activity can be oncogenic and alter chemotherapy response, making eIF4F an attractive antineoplastic target. Here, we combine a newly developed inducible RNAi platform and pharmacological targeting of eIF4F activity to define a critical role for endogenous eIF4F in Myc-dependent tumor initiation. We find elevated Myc levels are associated with deregulated eIF4F activity in the prelymphomatous stage of the Eμ-Myc lymphoma model. Inhibition of eIF4F is synthetic lethal with elevated Myc in premalignant pre-B/B cells resulting in reduced numbers of cycling pre-B/B cells and delayed tumor onset. At the organismal level, eIF4F suppression affected a subset of normal regenerating cells, but this was well tolerated and rapidly and completely reversible. Therefore, eIF4F is a key Myc client that represents a tumor-specific vulnerability. © 2012 The Authors.
Keywords: nonhuman; cancer staging; protein function; animal cell; mouse; animal tissue; complex formation; apoptosis; protein protein interaction; protein targeting; animal experiment; animal model; rna interference; in vivo study; b lymphocyte; carcinogenesis; eukaryota; myc protein; lymphoma; cell regeneration; mitosis inhibition; initiation factor 4f
Journal Title: Cell Reports
Volume: 1
Issue: 4
ISSN: 2211-1247
Publisher: Cell Press  
Date Published: 2012-04-19
Start Page: 325
End Page: 333
Language: English
DOI: 10.1016/j.celrep.2012.02.010
PROVIDER: scopus
PMCID: PMC3346676
PUBMED: 22573234
DOI/URL:
Notes: --- - "Export Date: 4 June 2012" - "Source: Scopus"
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  1. Scott W Lowe
    173 Lowe