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J Biol Chem. 2014 Dec 5;289(49):34065-73. doi: 10.1074/jbc.M114.604041. Epub 2014 Oct 15.

Cellular retinoic acid-binding protein 2 inhibits tumor growth by two distinct mechanisms.

Author information

1
From the Departments of Pharmacology and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
2
From the Departments of Pharmacology and.
3
From the Departments of Pharmacology and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195 Nutrition, Case Western Reserve University School of Medicine and nxn51@case.edu.

Abstract

Cellular retinoic acid-binding protein 2 (CRABP2) potently suppresses the growth of various carcinomas, but the mechanism(s) that underlies this activity remains incompletely understood. CRABP2 displays two distinct functions. The classical function of this protein is to directly deliver retinoic acid (RA) to RA receptor (RAR), a nuclear receptor activated by this hormone, in turn inducing the expression of multiple antiproliferative genes. The other function of the protein is exerted in the absence of RA and mediated by the RNA-binding and stabilizing protein HuR. CRABP2 directly binds to HuR, markedly strengthens its interactions with target mRNAs, and thus increases their stability and up-regulates their expression. Here we show that the anticarcinogenic activities of CRABP2 are mediated by both of its functions. Transcriptome analyses revealed that, in the absence of RA, a large cohort of transcripts is regulated in common by CRABP2 and HuR, and many of these are involved in regulation of oncogenic properties. Furthermore, both in cultured cells and in vivo, CRABP2 or a CRABP2 mutant defective in its ability to cooperate with RAR but competent in interactions with HuR suppressed carcinoma growth and did so in the absence of RA. Hence, transcript stabilization by the CRABP2-HuR complex significantly contributes to the ability of CRABP2 to inhibit tumorigenesis. Surprisingly, the observations also revealed that HuR regulates the expression of multiple genes involved in nuclear pore formation and is required for nuclear import of CRABP2 and for transcriptional activation by RAR. The data thus point at a novel function for this important protein.

KEYWORDS:

Cancer Biology; HuR; Nuclear Import/Export; Nucleus; RNA-binding Protein; Retinoic Acid; Retinoid-binding Protein

PMID:
25320093
PMCID:
PMC4256341
DOI:
10.1074/jbc.M114.604041
[Indexed for MEDLINE]
Free PMC Article

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