Insulin-like growth factor factor binding protein-2 is a novel mediator of p53 inhibition of insulin-like growth factor signaling.
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.
Grimberg
Adda
A
Department of Pediatrics, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Pennsylvania 19104-4318, USA. grimberg@email.chop.edu
Coleman
Carrie M
CM
Shi
Zonggao
Z
Burns
Timothy F
TF
MacLachlan
Timothy K
TK
Wang
Wenge
W
El-Deiry
Wafik S
WS
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*
D018971:Insulin-Like Growth Factor Binding Protein 2; D018969:Insulin-Like Growth Factor Binding Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases