Cell cycle-coupled variation in topoisomerase IIα mRNA is regulated by the 3′-untranslated region: Possible role of redox-sensitive protein binding in mRNA accumulation

Prabhat C. Goswami*, Jamie Sheren, Lee D. Albee, Azemat Parsian, Julia E. Sim, Lisa A. Ridnour, Ryuji Higashikubo, David Gius, Clayton R. Hunt, Douglas R. Spitz

*Corresponding author for this work

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Mammalian topoisomerase IIα (Topo II) is a highly regulated enzyme essential for many cellular processes including the G2 cell cycle checkpoint. Because Topo II gene expression is regulated posttranscriptionally during the cell cycle, we investigated the possible role of the 3′-untranslated region (3′-UTR) in controlling Topo II mRNA accumulation. Reporter assays in stably transfected cells demonstrated that, similar to endogenous Topo II mRNA levels, the mRNA levels of reporter genes containing the Topo II 3′-UTR varied during the cell cycle and were maximal in S and G2/M relative to G1. Topo II 3′-UTR sequence analysis and RNA-protein binding assays identified a 177-nucleotide (base pairs 4772-4949) region containing an AUUUUUA motif sufficient for protein binding. Multiple proteins (84, 70, 44, and 37 kDa) bound this region, and the binding of 84- and 37-kDa (tentatively identified as the adenosine- or uridinerich element-binding factor AUF1) proteins was enhanced in G′1, correlating with decreased Topo II mRNA levels. The binding activity was enhanced in cellular extracts or cells treated with thiol-reducing agents, and increased binding correlated with decreased Topo II mRNA levels. These results support the hypothesis that cell cycle-coupled Topo II gene expression is regulated by interaction of the 3′-UTR with redox-sensitive protein complexes.

Original languageEnglish (US)
Pages (from-to)38384-38392
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number49
DOIs
StatePublished - Dec 8 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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