DYSREGULATION OF THE TYPE-1 IGF RECEPTOR AS A PARADIGM IN TUMOR PROGRESSION

The Type 1 IGF receptor plays a critical role in cell progression. Dur ing normal ontogeny it is expressed by every proliferating cell, where it functions as a potent cell survival agent. Disruption of the Type 1 IGF receptor gene by homologous recombination results in severely gr owth retarded animals which invariably die at birth. Most importantly, fibroblasts derived from mice embryos lacking the receptor cannot be transformed by any of a number of oncogenes, indicating that the Type 1 IGF receptor displays potent mitogenic and antiapoptotic activities. A number of transcription factors have been identified that control t he expression of the IGF receptor promoter, thus stimulating cellular proliferation. On the other hand, certain tumour suppressors including p53 and WT1 were shown to repress the activity of the IGF receptor pr omoter. Mutant forms of these and other tumour suppressors are potenti ally impaired in their ability to suppress expression of the IGF recep tor gene, thus helping to expand neoplastic populations. (C) 1998 Publ ished by Elsevier Science Ireland Ltd. All rights reserved.