Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high ROS levels

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Abstract
Uncontrolled accumulation of reactive oxygen species (ROS) causes oxidative stress and induces harmful effects. Both high ROS levels and p53 mutations are frequent in human cancer. Mutant p53 forms are known to actively promote malignant growth. However, no mechanistic details are known about the contribution of mutant p53 to excessive ROS in cancer cells. Herein we examined the effect of p53R273H, a commonly occurring mutated p53 form, on the expression of phase 2 ROS detoxifying enzymes, and on the ability of cells to readopt a reducing environment after exposure to oxidative stress. Our data suggest that p53R273H mutant interferes with the normal response of human cells to oxidative stress. We show here that upon oxidative stress mutant p53R273H attenuates the activation and function of NF-E2-related factor 2 (NRF2), a transcription factor that induces antioxidant response. This effect of mutant p53 is manifested by decreased expression of phase 2 detoxifying enzymes NQO1 and HO-1 and high ROS levels. These findings were observed in several human cancer cell lines highlighting the general nature of this phenomenon. The failure of p53R273H mutant-expressing cells to restore a reducing oxidative environment was accompanied by increased survival, a known consequence of mutant p53 expression. These activities are attributable to mutant p53R273H gain of function and may underlie its well-documented oncogenic nature in human cancer.

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