Article

Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci

Department of Radiation Oncology and Department of Pediatrics, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2011; 108(39):16259-64. DOI: 10.1073/pnas.1113884108
Source: PubMed

ABSTRACT

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.

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Available from: Zhaohui Feng, Mar 19, 2015
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    • "Also, p53 represses the transcription of pyruvate dehydrogenase kinase 2 (PDK2) involved in PDH inactivation in MCF-7 and HCT116 cancer cell lines [9]. In addition, two proteins directly regulated by p53, AIF (apoptosis inhibitor factor) and Parkin (a RBR E3 ubiquitin protein ligase) are involved in protein expression and functioning of NADH dehydrogenase (respiratory chain complex I) and PDH activation (35%) [10] [11] which in turn, increase OxPhos flux. Although the action mechanisms associated with the p53 activation on energy pathways have not been elucidated in tumor cells, it has been suggested for non-tumor cells that p53 increases mtDNA stabilization and transcrip- A C C E P T E D M A N U S C R I P T "
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    ABSTRACT: The role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondrial enzyme contents, mitochondrial electrical potential (ΔΨm) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti-mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, ΔΨm and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-α, a p53-inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2-5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53-HIF-1α complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O2 level.
    Full-text · Article · Oct 2015 · Biochimica et Biophysica Acta
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    • "b) Oncogene activation and loss of tumor suppressor genes, where p53 plays an important role in regulating glycolysis and anabolic pathways branching off glycolysis from glycolytic intermediates . PARK2 or parkin (a Parkinson's disease-associated gene) has been identified as a p53 target gene which acts as a tumor suppressor gene and its deficiency in cancer cells results in promoting the Warburg effect and the cancer cell proliferation [5]. c) Mitochondrial dysfunction in cancer cells including increased levels of succinate and fumarate which shift energy production to glycolysis, strongly supporting Warburg's hypothesis [6]. "

    Full-text · Article · Apr 2015
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    • "b) Oncogene activation and loss of tumor suppressor genes, where p53 plays an important role in regulating glycolysis and anabolic pathways branching off glycolysis from glycolytic intermediates . PARK2 or parkin (a Parkinson's disease-associated gene) has been identified as a p53 target gene which acts as a tumor suppressor gene and its deficiency in cancer cells results in promoting the Warburg effect and the cancer cell proliferation [5]. c) Mitochondrial dysfunction in cancer cells including increased levels of succinate and fumarate which shift energy production to glycolysis, strongly supporting Warburg's hypothesis [6]. "
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    ABSTRACT: The Warburg effect means higher glucose uptake of cancer cells compared to normal tissues, whereas a smaller fraction of this glucose is employed for oxidative phosphorylation. With the advent of high throughput technologies and computational systems biology, cancer cell metabolism has been reinvestigated over the last decades toward identifying various events underlying “how” and “why” a cancer cell employs aerobic glycolysis. Significant progress has been shaped to revise the Warburg effect. In this study, we have integrated the gene expression of 13 different cancer cells with the genome-scale metabolic network of human (Recon1) based on the E-Flux method, and analyzed them based on constraint-based modeling. Results show that regardless of significant up- and down-regulated metabolic genes, the distribution of metabolic changes is similar in different cancer types. These findings support the theory that the Warburg effect is a consequence of metabolic adaptation in cancer cells.
    Full-text · Article · Mar 2015 · Genomics
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