DBI-1, a Novel Gene Related to the Notch Family, Modulates Mitogenic Response to Insulin-like Growth Factor 1

The insulin-like growth factor 1 (IGF-1) receptor has been found to transform fibroblast cells when overexpressed. The removal of 108 aa from the C-terminus of the IGF-1 receptor abolishes the transforming ability of the receptor without affecting its ability to induce cell growth. The availability of this mutant receptor provides a means to examine the changes in gene expression which take place during transformation, solely in response to an increased number of IGF-1 receptors. Using differential display, we have examined differences in gene expression between cells expressing a wild-type, transforming IGF-1 receptor and cells expressing a C-terminally truncated, nontransforming IGF-1 receptor. We have cloned a novel 6.3-kb cDNA transcript (DBI-1) which is expressed at much lower levels in cells containing the wild-type IGF-1 receptor. The predicted protein sequence of DBI-1 contains seven EGF-like repeats, which bear >90% sequence identity to the rat Notch 2 protein. The cDNA also contains a potential DEAD box in the C-terminal region. The DBI-1 message is detected at relatively high levels in cardiac tissue and at lower levels in lung, liver, and kidney. Antibodies generated to a unique region of the DBI-1 protein recognize a protein of 88 kDa, which is localized in the nucleus. Overexpression of DBI-1 in cells which contain the wild-type IGF-1 receptor diminishes the mitogenic response to IGF-1.