CFIm25 regulates glutaminase alternative terminal exon definition to modulate MIR-23 function

Chioniso P. Masamha, Zheng Xia, Natoya Peart, Scott Collum, Wei Li, Eric J. Wagner, Ann Bin Shyu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Alternative polyadenylation (APA) and alternative splicing (AS) provide mRNAs with the means to avoid microRNA repression through selective shortening or differential usage of 3′UTRs. The two glutaminase (GLS) mRNA isoforms, termed KGA and GAC, contain distinct 3′UTRs with the KGA isoform subject to repression by miR-23. We show that depletion of the APA regulator CFIm25 causes a strong shift to the usage of a proximal poly(A) site within the KGA 3′UTR and also alters splicing to favor exclusion of the GAC 3′UTR. Surprisingly, we observe that while miR-23 is capable of down-regulating the shortened KGA 3′UTR, it has only minor impact on the full-length KGA 3′UTR, demonstrating that additional potent negative regulation of GLS expression exists beyond this single microRNA targeting site. Finally, we show that the apoptosis induced upon downregulation of the GAC isoform can be alleviated through concurrent reduction in CFIm25 expression, revealing the sensitivity of glutaminase expression to the levels of RNA processing factors. These results exemplify the complex interplay between RNA processing and microRNA repression in controlling glutamine metabolism in cancer cells.

Original languageEnglish (US)
Pages (from-to)830-838
Number of pages9
JournalRNA
Volume22
Issue number6
DOIs
StatePublished - Jun 2016

Keywords

  • Alternative polyadenylation
  • C-Myc
  • Cell growth
  • Glutaminase
  • Glutamine addiction
  • MiRNA

ASJC Scopus subject areas

  • Molecular Biology

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