Hmgi-c is a member of a novel, developmentally regulated gene family. It is responsible for the pygmy (pg) mutation in mouse and the human homologue is disrupted in a number of tumors. Therefore, this proposal is an attempt to understand the function of Hmgi-c and its role in the interdependent processes of proliferation and tumorigenesis. Based on the human tumor studies, the first specific aim will investigate the nature of the HMGI-C gene products required in tumorigenesis. Transgenic mice will be generated that harbor various HMGI-C transgenes whose structure is similar to that seen in human tumors. Transgenic mice which express wildtype HMGI-C in an inappropriate cell type will be analyzed for tumor formation and the tumors characterized for activation of the endogenous Hmgi-c alleles. Tissue culture studies imply that HMGI-C is necessary for tumorigenesis. Therefore, the second aim will examine the susceptibility of the pg mouse mutant to tumorigenesis by different oncogenic stimuli in various tissues.
The third aim will analyze the effect of Hmgi-c expression on proliferation and the cell cycle. This will be performed on pg and wildtype embryonic fibroblasts grown under different culture conditions. Finally, in order to elucidate the molecular components of the Hmgi-c pathway, putative target genes will be identified by differential display. The long term objectives are to understand the role of Hmgi-c in growth and development. This will ultimately explain the phenotype of the pygmy mouse and how its disruption or deregulation leads to tumorigenesis including uterine leiomyoma, a major cause of hysterectomy in humans.
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