A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis.
Transgenic mice expressing the simian virus-40 large T-antigen (Tag) under the control of the insulin gene regulatory region offer a useful model for tumorigenesis. All the islets of Langerhans express Tag, although there is at first no aberrant proliferation. Over half of the islets become hyperplastic, however, and neovascularization of a further subset (about 10%)3 leads eventually to formation of highly vascularized solid tumours in 1-2% of islets by about 14 weeks of age. Here we show that the initial proliferative switch is correlated with focal activation of insulin-like growth factor II (IGF-II). Transfection with an antisense oligonucleotide to the IGF-II messenger RNA interferes with tumour cell proliferation in vitro, and transgenic mice homozygous for a disruption of the IGF-II gene develop tumours with reduced malignancy and a higher incidence of apoptosis. Several signals, in this case including an oncoprotein and a growth/survival factor, thus appear to be needed to elicit hyperproliferation.
Christofori
G
G
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0534.
Naik
P
P
Hanahan
D
D
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D017209:Apoptosis; D001483:Base Sequence; D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D017403:In Situ Hybridization; D007328:Insulin / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D007340:Insulinoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D009857:Oncogenes; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen; D016372:RNA, Antisense / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000952:Antigens, Polyomavirus Transforming; D007328:Insulin; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D018809:Proliferating Cell Nuclear Antigen; D016372:RNA, Antisense; D007335:Insulin-Like Growth Factor II