Protein ligands to HuR modulate its interaction with target mRNAs in vivo

Christopher M. Brennan, Imed Gallouzi, Joan A. Steitz

Research output: Contribution to journalArticle

284 Citations (Scopus)

Abstract

AU-rich elements (AREs) present in the 3' untranslated regions of many protooncogene, cytokine, and lymphokine messages target them for rapid degradation. HuR, a ubiquitously expressed member of the ELAV (embryonic lethal abnormal vision) family of RNA binding proteins, selectively binds AREs and stabilizes ARE-containing mRNAs in transiently transfected cells. Here, we identify four mammalian proteins that bind regions of HuR known to be essential for its ability to shuttle between the nucleus and the cytoplasm and to stabilize mRNA: SETα, SETβ, pp32, and acidic protein rich in leucine (APRIL). Three have been reported to be protein phosphatase 2A inhibitors. All four ligands contain long, acidic COOH-terminal tails, while pp32 and APRIL share a second motif: rev-like leucine-rich repeats in their NH2-terminal regions. We show that pp32 and APRIL are nucleocytoplasmic shuttling proteins that interact with the nuclear export factor CRM1 (chromosomal region maintenance protein 1). The inhibition of CRM1 by leptomycin B leads to the nuclear retention of pp32 and APRIL, their increased association with HuR, and an increase in HuR's association with nuclear poly(A)+ RNA. Furthermore, transcripts from the ARE-containing c-fos gene are selectively retained in the nucleus, while the cytoplasmic distribution of total poly(A)+ RNA is not altered. These data provide evidence that interaction of its ligands with HuR modulate HuR's ability to bind its target mRNAs in vivo and suggest that CRM1 is instrumental in the export of at least some cellular mRNAs under certain conditions. We discuss the possible role of these ligands upstream of HuR in pathways that govern the stability of ARE-containing mRNAs.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalJournal of Cell Biology
Volume151
Issue number1
DOIs
Publication statusPublished - 2 Oct 2000
Externally publishedYes

Fingerprint

AU Rich Elements
Ligands
Messenger RNA
Leucine
Proteins
Aptitude
Maintenance
fos Genes
Protein Phosphatase 2
RNA-Binding Proteins
Cell Nucleus Active Transport
Lymphokines
3' Untranslated Regions
Cytoplasm
Cytokines

Keywords

  • AU-rich elements
  • CRM1
  • Nucleocytoplasmic shuttling
  • Protein phosphatase inhibitors
  • RNA stability

ASJC Scopus subject areas

  • Cell Biology

Cite this

Protein ligands to HuR modulate its interaction with target mRNAs in vivo. / Brennan, Christopher M.; Gallouzi, Imed; Steitz, Joan A.

In: Journal of Cell Biology, Vol. 151, No. 1, 02.10.2000, p. 1-13.

Research output: Contribution to journalArticle

Brennan, Christopher M. ; Gallouzi, Imed ; Steitz, Joan A. / Protein ligands to HuR modulate its interaction with target mRNAs in vivo. In: Journal of Cell Biology. 2000 ; Vol. 151, No. 1. pp. 1-13.
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