Tumor-associated mutant forms of p53 can exert an antiapoptotic gain of function activity, which confers a selective advantage upon tumor cells harboring such mutations. We report that mutant p53 suppresses the expression of the MSP (MST-1/HGFL) gene, encoding the ligand of the receptor tyrosine kinase RON, implicated in a variety of cellular responses. Mutant p53 associates with the MSP gene promoter and represses its transcriptional activity, leading to a decrease in mRNA levels and a subsequent decrease in the levels of secreted MSP protein. Forced downregulation of MSP expression in H1299 cells, derived from a large-cell lung carcinoma, confers increased resistance against etoposide-induced cell death. These antiapoptotic consequences of MSP downregulation seemingly conflict with the well-documented ability of the RON receptor to promote cell survival and tumor progression when aberrantly hyperactive. Yet, they are consistent with the fact that reduced MSP expression was observed in many types of human cancer, including large-cell lung carcinoma. Thus, repression of MSP gene expression by mutant p53 may contribute to oncogenesis in a cell type-specific manner.