title: p53-Dependent and p53-independent induction of insulin-like growth factor binding protein-3 by deoxyribonucleic acid damage and hypoxia.
abstract: IGF binding protein (IGFBP)-3, the principal carrier of IGFs in the circulation, contributes to both endocrine and autocrine/paracrine growth control; it can be induced by GH, cytokines, retinoic acid, and tumor suppressors. Induction of IGFBP-3 by the tumor suppressor p53 has been shown in various models that directly manipulate p53 activity. However, the physiologic settings under which this induction occurs have not been established. DNA damage and hypoxia are two important physiologic activators of p53. We have demonstrated for the first time that IGFBP-3 is an in vivo target of p53 in response to ionizing radiation. This effect was tissue specific. Furthermore, we demonstrated that genotoxic drugs could increase IGFBP-3 protein levels and secretion in tumor cell lines in a p53-independent manner. Finally, we have established that IGFBP-3 induction under hypoxic conditions is independent of p53 in tumor cell lines derived form multiple tissue types. Thus, IGFBP-3 is induced by physiologic conditions that also induce p53, although p53 is not always required. Because IGFBP-3 can inhibit growth and induce apoptosis in IGF-dependent and IGF-independent manners, its induction by DNA damage and hypoxia suggest IGFBP-3 plays a role in the physiologic protection against aberrant cell growth.
authors.affiliation: Division of Pediatric Endocrinology, The Children's Hospital of Philadelphia, Abramson Research Center, Room 802, 3615 Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4318, USA. grimberg@e-mail.chop.edu
authors.forename: Adda
authors.initials: A
authors.lastname: Grimberg
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Coleman
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Burns
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Himelstein
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Koch
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D003907:Dexamethasone / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D008175:Lung Neoplasms; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D003907:Dexamethasone; D004317:Doxorubicin