Human breast cancer MCF-7 cells, growth-arrested by serum starvation, were stimulated with recombinant human insulinlike growth factor-1 (IGF-I). An increase in DNA synthesis was induced 20 hr later, which was as effective as that induced by serum. The increase in DNA synthesis was significantly inhibited either by antibody to the IGF-I receptor or by the tyrosine kinase inhibitor, methyl-2,5-dihydroxycinnamate (2,5-MeC). The IGF-l-induced DNA synthesis coincided with an elevated level of phosphorylation of p53 on tyrosine and an alteration in the subcellular distribution of the protein from the nucleus to the cytoplasm. Whereas the increases in DNA synthesis and p53 phosphorylation were inhibited by antibody to the IGF-I receptor and by 2,5-Mec, the nuclear exclusion of p53 was prevented by the antibody and also, although not significantly, by 2,5-Mec. The results suggest that growth stimulation of MCF-7 cells by IGF-I is accompanied by tyrosine phosphorylation and nuclear exclusion of p53.