c-Myc deregulation induces mRNA capping enzyme dependency

Olivia Lombardi, Dhaval Varshney, Nicola M. Phillips, Victoria H. Cowling (Lead / Corresponding author)

Research output: Contribution to journalArticle

7 Citations (Scopus)
148 Downloads (Pure)

Abstract

c-Myc is a potent driver of many human cancers. Since strategies for directly targeting c-Myc protein have had limited success, upstream regulators and downstream effectors of c-Myc are being investigated as alternatives for therapeutic intervention. c-Myc regulates transcription and formation of the mRNA cap, which is important for transcript maturation and translation. However, the direct mechanism by which c-Myc upregulates mRNA capping is unclear. mRNA cap formation initiates with the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide, catalysed by mRNA capping enzyme (CE/RNGTT). Here we report that c-Myc increases the recruitment of catalytically active CE to RNA polymerase II and to its target genes. c-Myc-induced target gene expression, cell proliferation and cell transformation is highly dependent on CE, but only when c-Myc is deregulated. Cells retaining normal control of c-Myc expression are insensitive to repression of CE. c-Myc expression is also dependent on CE. Therefore, inhibiting CE provides an attractive route for selective therapeutic targeting of cancer cells which have acquired deregulated c-Myc.
Original languageEnglish
Pages (from-to)82273-82288
Number of pages16
JournalOncotarget
Volume7
Issue number50
Early online date16 Oct 2016
DOIs
Publication statusPublished - 16 Oct 2016

Keywords

  • c-Myc
  • mRNA cap
  • transcription
  • translation
  • cell proliferation

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    Investigating the role of mRNA capping enzyme in C-MYC function

    Author: Lombardi, O., 2017

    Supervisor: Cowling, V. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy

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    Cowling, Victoria

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