International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 144 - COMBINED EFFECTS OF INSULIN-LIKE GROWTH FACTOR 2 EXCESS AND TUMOUR SUPPRESSOR LOSS IN OVERGROWTH AND CANCER

TE Crew
University of Bath

Bennett W R, Ward A
University of Bath

Insulin-like growth factor 2 (IGF2) is implicated in overgrowth diseases and tumour formation in humans and transgenic animals.  We have investigated whether, along with the effects of IGF2, inactivation of one or more tumour suppressor genes are involved in the transition from overgrowth to cancer.  Transgenic mice, overexpressing IGF2 under the control of a keratin gene promoter, show overgrowth of the skin and colon but do not develop tumours.  In mice with both this transgene and inactivation of the tumour suppressor gene p53, the skin becomes markedly more hyperplastic.  Excess IGF2 also appears to change the spectrum of tumours seen in the p53 knockout mice from mainly thymic lymphomas to include skin papillomas.  The IGF2 gene is located on human chromosome 11p15 (chromosome 7 in mouse), in close proximity to the cyclin dependent kinase (cdk) inhibitor p57KIP2.  Mutation/mis-regulation of both of these genes occur in the overgrowth disorder Beckwith Wiedemann Syndrome (BWS).  One proposed route for the molecular pathogenesis of BWS is overexpression of a paternally expressed gene (for example, IGF2) and/or the deficiency of a maternally expressed gene (for example, p57KIP2).  We have attempted to create transgenic mice overexpressing IGF2 and lacking functional p57KIP2 but our efforts to assess potential tumour incidence in these mice have been hampered by poor animal survival, despite inbreeding to the 129 strain background.  Additional experiments have concentrated on examining the effects of overexpression of IGF2 combined with the lack of another cdk inhibitor, p27KIP1, which belongs to the same family as p57KIP2.


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