Regulation of energy metabolism is a novel function of p53 in
tumor suppression. Parkin (PARK2), a
Parkinson disease-associated gene, is a potential
tumor suppressor whose expression is frequently diminished in
tumors. Here Parkin was identified as a p53 target gene that is an important mediator of p53's function in regulating energy metabolism. The human and mouse Parkin genes contain functional p53 responsive elements, and p53 increases the transcription of Parkin in both humans and mice. Parkin contributes to the function of p53 in
glucose metabolism; Parkin deficiency activates glycolysis and reduces mitochondrial respiration, leading to the Warburg effect. Restoration of Parkin expression reverses the Warburg effect in cells. Thus, Parkin deficiency is a novel mechanism for the Warburg effect in
tumors. Parkin also contributes to the function of p53 in
antioxidant defense. Furthermore, Parkin deficiency sensitizes mice to γ-irradiation-induced
tumorigenesis, which provides further direct evidence to support a role of Parkin in
tumor suppression. Our results suggest that as a novel component in the p53 pathway, Parkin contributes to the functions of p53 in regulating energy metabolism, especially the Warburg effect, and
antioxidant defense, and thus the function of p53 in
tumor suppression.