title: Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling.
abstract: The p53 tumor suppressor induces cellular growth arrest and apoptosis in response to DNA damage by transcriptionally activating or repressing target genes and also through protein-protein interactions and direct mitochondrial activities. In 1995, insulin-like growth factor binding protein (IGFBP)-3 was identified as one of the genes transcriptionally activated by p53. IGFBP-3 is one of six closely related IGFBP's, with additional IGFBP-related proteins belonging to the IGFBP superfamily. Here we show that IGFBP-2 is also a p53 target. Like IGFBP-3, IGFBP-2 secretion is reduced when p53+/+ lung cancer cells are transfected with human papillomavirus E6, which targets p53 for degradation. IGFBP-2 mRNA is induced by irradiation in vivo in a p53-dependent manner. p53 protein binds IGFBP-2 intronic sequences in an electrophoretic mobility shift assay, and activates transcription in a luciferase assay. Loss of IGFBP-2 inhibits the ability of p53 to inhibit the activation of extracellular signal-regulated kinase (ERK)1 by IGF-I. Thus, p53 effects on the IGF axis are more complex than previously appreciated, and overall transform the axis from IGF-mediated mitogenesis to growth inhibition and apoptosis. This has significant implications for how growth hormone and IGF-I can induce growth without also inducing cancer.
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Pennsylvania 19104-4318, USA. grimberg@email.chop.edu
authors.forename: Adda
authors.initials: A
authors.lastname: Grimberg
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Coleman
authors.forename: Zonggao
authors.initials: Z
authors.lastname: Shi
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Burns
authors.forename: Timothy K
authors.initials: TK
authors.lastname: MacLachlan
authors.forename: Wenge
authors.initials: W
authors.lastname: Wang
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division; D017930:Genes, Reporter; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D018969:Insulin-Like Growth Factor Binding Proteins / Q000502:physiology*; D007438:Introns; D008156:Luciferases / Q000235:genetics; D008957:Models, Genetic; D009369:Neoplasms / Q000473:pathology / Q000517:prevention & control; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases