title: Cellular retinoic acid-binding protein 2 inhibits tumor growth by two distinct mechanisms.
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.
authors.affiliation: From the Departments of Pharmacology and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Vreeland
authors.affiliation: From the Departments of Pharmacology and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors.forename: Liraz
authors.initials: L
authors.lastname: Levi
authors.affiliation: From the Departments of Pharmacology and Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: From the Departments of Pharmacology and.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Berry
authors.affiliation: 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.
authors.forename: Noa
authors.initials: N
authors.lastname: Noy
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D000067780:ELAV-Like Protein 1; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin; D008156:Luciferases
keywords: Cancer Biology; HuR; Nuclear Import/Export; Nucleus; RNA-binding Protein; Retinoic Acid; Retinoid-binding Protein