In this study, we demonstrate that protective autophagy is involved in the 5-FU resistance of p53-deficient or mutant p53-expressing colon cancer cells and that 5-FU-mediated JNK activation in HCT116 p53−/− and HT-29 cells promotes autophagy as a pro-survival effect, probably by inducing Bcl-2 phosphorylation. The gene discussed is TP53; the disease is colonic neoplasm.