title: RNA-binding protein insulin-like growth factor mRNA-binding protein 3 (IMP-3) promotes cell survival via insulin-like growth factor II signaling after ionizing radiation.
abstract: Ionizing radiation (IR) induces proapoptotic gene expression programs that inhibit cell survival. These programs often involve RNA-binding proteins that associate with their mRNA targets to elicit changes in mRNA stability and/or translation. The RNA-binding protein IMP-3 is an oncofetal protein overexpressed in many human malignancies. IMP-3 abundance correlates with tumor aggressiveness and poor prognosis. As such, IMP-3 is proving to be a highly significant biomarker in surgical pathology. Among its many mRNA targets, IMP-3 binds to and promotes translation of insulin-like growth factor II (IGFII) mRNA. Our earlier studies showed that reducing IMP-3 abundance with siRNAs reduced proliferation of human K562 chronic myeloid leukemia cells because of reduced IGF-II biosynthesis. However, the role of IMP-3 in apoptosis is unknown. Here, we have used IR-induced apoptosis of K562 cells as a model to explore a role for IMP-3 in cell survival. Knockdown of IMP-3 with siRNA increased susceptibility of cells to IR-induced apoptosis and led to reduced IGF-II production. Gene reporter assays revealed that IMP-3 acts through the 5' UTR of IGFII mRNA during apoptosis to promote translation. Finally, culture of IR-treated cells with recombinant IGF-II partially reversed the effects of IMP-3 knockdown on IR-induced apoptosis. Together, these results indicate that IMP-3 acts in part through the IGF-II pathway to promote cell survival in response to IR. Thus, IMP-3 might serve as a new drug target to increase sensitivity of CML cells or other cancers to IR therapy.
authors.affiliation: Department of Molecular Genetics, Microbiology, and Immunology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Baisong
authors.initials: B
authors.lastname: Liao
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.forename: Gary
authors.initials: G
authors.lastname: Brewer
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002470:Cell Survival; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D020014:K562 Cells; D009687:Nuclear Proteins; D020011:Protective Agents; D034741:RNA, Small Interfering / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000502:physiology*; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects*
chemical_list: C121310:ACIN1 protein, human; C498780:IGF2BP3 protein, human; D009687:Nuclear Proteins; D020011:Protective Agents; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D007335:Insulin-Like Growth Factor II