title: Insulin-like growth factor-I receptor is suppressed through transcriptional repression and mRNA destabilization by a novel energy restriction-mimetic agent.
abstract: Insulin-like growth factor-I receptor (IGF-IR) represents one of the major targets by which dietary or chemically induced energy restriction mediates chemopreventive effects in animal tumor models. However, the mechanism underlying this cellular response remains unclear. In the course of investigating the suppressive effect of the energy restriction-mimetic agent CG-5 on IGF-IR expression in prostate cancer cells, we identified a novel posttranscriptional mechanism by which the RNA-binding protein human antigen R (HuR) regulates IGF-IR expression through messenger RNA (mRNA) stabilization. Previously, we demonstrated that Sp1 and HuR proteins were concomitantly targeted for ubiquitin-dependent degradation by β-transducin repeat-containing protein in response to CG-5. Although this loss of Sp1 expression contributed to CG-5-mediated IGF-IR downregulation, enforced specific protein 1 (Sp1) expression could only partially protect cells from the drug effect. The small interfering RNA-mediated silencing of HuR suppressed IGF-IR expression by reducing mRNA stability, whereas ectopic HuR expression increased IGF-IR mRNA stability and protein expression and, when coexpressed with Sp1, blocked CG-5-mediated IGF-IR ablation. RNA pull-down and immunoprecipitation analyses indicated that HuR selectively bound to the distal region of the IGF-IR 3' untranslated region (UTR), whereas no interaction with the 5'UTR was noted. Evaluation of a series of truncated HuR mutants revealed that the RNA recognition motifs (RRM2 and RRM3) were involved in IGF-IR 3'UTR binding and the consequent increase in IGF-IR mRNA stability. Although these data contrast with a previous report that HuR acted as a translation repressor of IGF-IR mRNA through 5'UTR binding, our finding is consistent with the reported oncogenic role of HuR in conferring stability to target mRNAs encoding tumor-promoting proteins.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43221, USA and.
authors.forename: Po-Chen
authors.initials: PC
authors.lastname: Chu
authors.forename: Samuel K
authors.initials: SK
authors.lastname: Kulp
authors.forename: Ching-Shih
authors.initials: CS
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D020121:5' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D051959:ELAV Proteins / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D051959:ELAV Proteins; D007136:Immunoglobulins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C090698:SP1 antigen; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D017526:Receptor, IGF Type 1