We developed a high-titer amphotropic retroviral vector that expresses mutant (Ala143) human p53 to test directly the response of genetically normal human epithelial cells to p53 mutation. Contrary to our prediction, we found that in pancreatic epithelium (whose tumors display a high frequency of p53 mutation) but not in thyroid (whose tumors show an exceptionally low mutation frequency), expression of mutant p53 induced a dramatic, though self-limiting, proliferative response. This result questions the assumption that p53 mutation is relevant only to the later stages of tumorigenesis.