Increased IGF-II protein affects p57kip2 expression in vivo and in vitro: implications for Beckwith-Wiedemann syndrome.

Abstract

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.

• Authors: V Grandjean, J Smith, P N Schofield, A C Ferguson-Smith
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 97 Issue 10 Pg. 5279-84 (May 09 2000) ISSN: 0027-8424 [Print] United States
• PMID: 10779549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CDKN1C protein, human
• Cdkn1c protein, mouse
• Cyclin-Dependent Kinase Inhibitor p57
• Enzyme Inhibitors
• Nuclear Proteins
• Insulin-Like Growth Factor II

Topics

• 3T3 Cells
• Animals
• Beckwith-Wiedemann Syndrome (genetics)
• Cells, Cultured
• Chromosome Mapping
• Chromosomes, Human, Pair 11
• Crosses, Genetic
• Cyclin-Dependent Kinase Inhibitor p57
• Embryo, Mammalian
• Enzyme Inhibitors
• Female
• Fibroblasts (cytology, physiology)
• Gene Expression Regulation (drug effects)
• Genomic Imprinting
• Humans
• Insulin-Like Growth Factor II (genetics, pharmacology, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred CBA
• Multigene Family
• Nuclear Proteins (genetics)