Department of Anatomy; University of Cambridge
In human and mouse, the IGF2 gene, localized on chromosome 11 and 7, respectively, is expressed from the paternal chromosome. This insulin-like growth factor plays an important role in embryonic growth. Increased IGF2 expression has been implicated in several human pathologies, such as the Beckwith-Wiedemann overgrowth syndrome and embryonal tumors. Human and mouse genetic data strongly suggest that another gene, p57KIP2, located in the same imprinted gene cluster on human chromosome 11 may also be involved in BWS. p57KIP2 is an inhibitor of cyclin-dependent kinase and is required for normal mouse embryonic development. Mutations in p57KIP2 have been identified in a small proportion of BWS patients.
The fact that alteration of one of these gene activities can produced the same syndrome (BWS) and the overlapping phenotypes observed in two different mutant mice, the p57Kip2 knock-out and the over-expressing-Igf2 mice have suggested a possible functional interaction between these two genes. In our study, we show that p57Kip2 RNA expression is reduced in Igf2 treated primary embryo fibroblasts in a dose-dependent manner. In addition, p57Kip2 expression is down regulated in mice with high circulatory Igf2. Furthermore, the reduction in p57Kip2 transcription observed in vitro and in vivo is reflected in the reduced protein level. These data suggest that the effects of IGF2 in BWS could, in part, be mediated by a decrease in p57KIP2 gene expression.