RNA-binding protein HuR autoregulates its expression by promoting alternative polyadenylation site usage

Weijun Dai, Gen Zhang, Eugene V. Makeyev*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)

Abstract

RNA-binding protein HuR modulates the stability and translational efficiency of messenger RNAs (mRNAs) encoding essential components of the cellular proliferation, growth and survival pathways. Consistent with these functions, HuR levels are often elevated in cancer cells and reduced in senescent and quiescent cells. However, the molecular mechanisms that control HuR expression are poorly understood. Here we show that HuR protein autoregulates its abundance through a negative feedback loop that involves interaction of the nuclear HuR protein with a GU-rich element (GRE) overlapping with the HuR major polyadenylation signal (PAS2). An increase in the cellular HuR protein levels stimulates the expression of long HuR mRNA species containing an AU-rich element (ARE) that destabilizes the mRNAs and thus reduces the protein production output. The PAS2 read-through occurs due to a reduced recruitment of the CstF-64 subunit of the pre-mRNA cleavage stimulation factor in the presence of the GRE-bound HuR. We propose that this mechanism maintains HuR homeostasis in proliferating cells. Since only the nuclear HuR is expected to contribute to the auto-regulation, our model may explain the longstanding observation that the increase in the total HuR expression in cancer cells often correlates with the accumulation of its substantial fraction in the cytoplasm.

Original languageEnglish
Pages (from-to)787-800
Number of pages14
JournalNucleic Acids Research
Volume40
Issue number2
Early online date24 Sept 2011
DOIs
Publication statusPublished - Jan 2012

Keywords

  • PRE-MESSENGER-RNA
  • POSTTRANSCRIPTIONAL GENE-REGULATION
  • CYTOPLASMIC SHUTTLING PROTEIN
  • STABILITY FACTOR HUR
  • AU-RICH ELEMENTS
  • PROGNOSTIC-FACTOR
  • CYCLOOXYGENASE-2 EXPRESSION
  • REPLICATIVE SENESCENCE
  • CELL-PROLIFERATION
  • OVARIAN-CARCINOMA

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