Transcript Stabilization by the RNA-Binding Protein HuR Is Regulated by Cellular Retinoic Acid-Binding Protein 2

Abstract

The RNA-binding protein HuR binds at 3′ untranslated regions (UTRs) of target transcripts, thereby protecting them against degradation. We show that HuR directly interacts with cellular retinoic acid-binding protein 2 (CRABP2), a protein known to transport RA from the cytosol to the nuclear retinoic acid receptor (RAR). Association with CRABP2 dramatically increases the affinity of HuR toward target mRNAs and enhances the stability of such transcripts, including that of Apaf-1, the major protein in the apoptosome. We show further that its cooperation with HuR contributes to the ability of CRABP2 to suppress carcinoma cell proliferation. The data show that CRABP2 displays antioncogenic activities both by cooperating with RAR and by stabilizing antiproliferative HuR target transcripts. The observation that CRABP2 controls mRNA stabilization by HuR reveals that in parallel to participating in transcriptional regulation, the protein is closely involved in posttranscriptional regulation of gene expression.

ACKNOWLEDGMENTS

We thank Ann Koehler for assistance with purification of recombinant proteins, Hua Lou (Case Western Reserve University) and Imed Gallouzi (McGill University) for HuR vectors, Cecile Rochette-Egly (IGBMC, Strasbourg, France) for CRABP2 antibodies, and Hiroyuki Kagechika (Tokyo Medical and Dental University) for LE540.

This work was supported by NIH grants DK060684 and CA166955 to N.N. A.C.V. was partially supported by NIH grant 5T32GM008803. The Cytometry and Imaging Microscopy Core Facility of the Case Comprehensive Cancer Center is supported by P30 CA43703.