title: Evidence that Igf2 down-regulation in postnatal tissues and up-regulation in malignancies is driven by transcription factor E2f3.
abstract: Insulin-like growth factor 2 (IGF2) is an important fetal growth factor. Its expression is dramatically down-regulated in multiple organs after birth but is frequently up-regulated in cancers. The mechanisms that drive down-regulation of IGF2 in postnatal tissues or the up-regulation in malignancy are unclear. We found evidence that E2F transcription factor 3 (E2F3) drives these changes in expression. E2f3 mRNA expression, protein expression, and binding to the Igf2 promoter all decreased with age postnatally in multiple mouse organs. In late juvenile hepatocytes, restoration of high E2f3 expression restored high Igf2 expression, indicating a causal relationship, but this induction did not occur in fetal hepatocytes, which already have high E2f3 and Igf2 expression. Transient expression of E2f3 in both HEK293 cells and in late juvenile hepatocytes were able to activate reporter constructs containing the mouse Igf2 promoter P2, which includes consensus E2F-binding sites. In humans, microarray data revealed declines in E2F3 and IGF2 expression with age similar to the mouse. In addition, E2F3-overexpressing human prostate and bladder cancers showed increased IGF2 expression, and levels of E2F3 and IGF2 mRNA in these cancers were positively correlated. Taken together, the findings suggest that down-regulation of E2f3 with age helps drive the dramatic decline in Igf2 expression in postnatal organs, and E2F3 overexpression in human cancers induces IGF2 overexpression.
authors.affiliation: Section on Growth and Development, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. luichunk@mail.nih.gov
authors.forename: Julian C
authors.initials: JC
authors.lastname: Lui
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Baron
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D015536:Down-Regulation; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D013997:Time Factors
chemical_list: D050699:E2F3 Transcription Factor; D007335:Insulin-Like Growth Factor II