Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome.
In both human and mouse, the Igf2 gene, localized on chromosomes 11 and 7, respectively, is expressed from the paternally inherited chromosome in the majority of tissues. Insulin-like growth factor-II (IGF-II) plays an important role in embryonic growth, and aberrant IGF2 expression has been documented in several human pathologies, such as Beckwith-Wiedemann syndrome (BWS), and a wide variety of tumors. Human and mouse genetic data strongly implicate another gene, CDKN1C (p57(kip2)), located in the same imprinted gene cluster on human chromosome II, in BWS. p57(KIP2) is a cyclin-dependent kinase inhibitor and is required for normal mouse embryonic development. Mutations in CDKN1C (p57(kip2)) have been identified in a small proportion of patients with BWS, and removal of the gene from mice by targeted mutagenesis produces a phenotype with elements in common with this overgrowth syndrome. Patients with BWS with biallelic expression of IGF2 or with a CDKN1C (p57(kip2)) mutation, as well as overlapping phenotypes observed in two types of mutant mice, the p57(kip2) knockout and IGF-II-overexpressing mice, strongly suggest that the genes may act in a common pathway of growth control in situations where Igf2 expression is abnormal. Herein, we show that p57(kip2) expression is reduced on IGF-II treatment of primary embryo fibroblasts in a dose-dependent manner. In addition, p57(kip2) expression is down-regulated in mice with high serum levels of IGF-II. These data suggest that the effects of increased IGF-II in BWS may, in part, be mediated through a decrease in p57(kip2) gene expression.
Grandjean
V
V
University of Cambridge, Department of Anatomy, Downing Street, CB2 3DY Cambridge, United Kingdom.
Smith
J
J
Schofield
P N
PN
Ferguson-Smith
A C
AC
D016475:3T3 Cells; D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D003433:Crosses, Genetic; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D018392:Genomic Imprinting; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D005810:Multigene Family; D009687:Nuclear Proteins / Q000235:genetics*
C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D007335:Insulin-Like Growth Factor II