Apoptosis of Tumor Cells A Soluble Insulin-like Growth Factor I Receptor That Induces

By a frame-shift mutation, we have engineered a human IGF-l receptor (IGF-IR) eDNA that produces a receptor 486 amino acids long (plus the 30 amino acids of the signal peptide). This receptor, which we have desig nated as 486/STOP, is partially secreted into the medium ofcells in culture and markedly inhibits the autophosphorylation of the endogenous IGF IRs as well as the activation of the signaling pathway. The 486/STOP receptor acts as a strong dominant negative for several growth functions: (a) it inhibits the growth of cells in monolayers; (b) it inhibits the growth of transformed cells in soft agar; (c) it induces extensive apoptosis in vivo; and (d) it inhibits tumorigenesis in syngeneic rats. This is the first dem onstration that a dominant negative of the IGF-IR can induce massive apoptosis of tumor cells in vivo.