Deregulated manganese superoxide dismutase expression and resistance to oxidative injury in p53-deficient cells

Loss of function of the tumor suppressor protein p53 represents a very freq uent event in human carcinogenesis, but the molecular mechanisms linking im paired p53 activity to increased cell malignancy are still incompletely und erstood. p53 is normally involved in both cell cycle control and the induct ion of cell death and is involved in the latter mainly through the transcri ptional regulation of pro- and antiapoptotic proteins, Reactive oxygen spec ies are known to be powerful inducers of p53 activity; moreover, they play a role in the execution of p53-dependent apoptosis. Here we show that trans formed mouse fibroblasts lacking p53 are significantly more resistant than wild-type (wt) controls to the cytotoxic effect of a number of pro-oxidant treatments. Interestingly, these cells also exhibit deregulated expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD), a protein known to protect cancer cells from the oxidative injury inflicted by antit umoral cytokines and anticancer drugs. MnSOD activity was also increased in liver tissue from p53-deficient mice in comparison with wt tissue. Transie nt transfection of nt p53 in HeLa cells Led to a significant reduction in s teady-state MnSOD mRNA levels and enzymatic activity, confirming that the e xpression of this antioxidant enzyme is negatively regulated by p53, Forced expression of MnSOD rendered HeLa cells resistant to p53-dependent cytotox ic treatments and, in cotransfection experiments, counteracted the growth-i nhibitory effect of p53, Taken together, these data identify MnSOD as a pot ential target for tumor suppressor protein p53 and underscore the relevance of MnSOD modulation in the contest of normal p53 functions because it is c onsistent with many reports of abnormally increased MnSOD expression in hum an cancers.