Role of Dietary Antioxidants in p53-Mediated Cancer Chemoprevention and Tumor Suppression

Figure 2

DNA damage and oncogenic signaling active the p53 tumor suppressor to maintain genomic stability and prevent transformation. Both the double-stranded DNA break and the single-stranded DNA break trigger the activation of p53 through ATM and ATR, respectively. Chk1 and Chk2 are selectively phosphorylated and activated by ATR and ATM, respectively. Oncogenic signaling produces the ARF tumor suppressor to inhibit the expression of MDM2 and MDMX. MDM2 and MDMX are the two negative regulators that function as an E3 ubiquitin ligase, which recognizes the N-terminal transcriptional activation domain (TAD) of p53, and as an inhibitor of p53 transcriptional activation. Therefore, under no stress or no DNA damage, p53 is kept inactive by the negative regulation by MDM2 and MDMX. Once activated, p53 induces antioxidant genes such as TIGAR, sestrin 1/2, GPx1, ALDH4, GLS2, and Parkin to repair the DNA. Growth arrest and DNA damage-inducible proteins such as GADD45, p21, Ypel3, and Pml are induced by p53 to cell cycle arrest and apoptotic genes, including DR5, Fas, PERP, Bcl-2, Bax, Noxa, and Puma for p53-mediated apoptosis. If the p53 gene is damaged, tumor suppression is severely reduced. Mutant p53 transactivates several genes, including MDR1, c-myc, PCNA, IL-6, IGF-1, FGF, EGFR, ASNS, and TERT. Mutant p53 promotes oncogenic genes, which lead to the progression of aggressive cancers. Abbreviations: ALDH4: aldehyde dehydrogenases; ARF: alternate reading frame; ASNS: asparagine synthetase; ATM: ataxia telangiectasia-mutated protein kinase; ATR: ATM-Rad3-related protein kinase; Bax: Bcl-2-associated X protein; Bcl-2: B-cell lymphoma 2; Chk1: checkpoint kinase 1; Chk2: checkpoint kinase 2; DR5: death receptor 5; EGFR: epidermal growth factor receptor; Fas: Fas cell surface death receptor; FGF: fibroblast growth factor; GADD45: growth arrest and DNA damage-inducible protein; GLS2: glutaminase 2; GPx1: glutathione peroxidase-1; IGF-1: insulin-like growth factor 1; MDM2: mouse double minute 2 homolog; MDMX: double minute X human homolog; MDR1: multiple drug resistance gene 1; Noxa: damage protein, a proapoptotic BH3-containing protein; p21: cyclin-dependent kinase inhibitor; p53: tumor suppressor; PCNA: proliferating cell nuclear antigen; PERP: p53 apoptosis effector related to PMP22; Pml: promyelocytic leukemia protein; Puma: p53 upregulated modulator of apoptosis; TERT: telomerase reverse transcriptase; TIGAR: TP53-inducible glycolysis and apoptosis regulator; Ypel3: Yippee-like 3.