Discovery of novel tumor suppressor p53 response elements using information theory

Lyakhov, Ilya; Krishnamachari, Annangarachari; Schneider, Thomas D.

doi:10.1093/nar/gkn189

Cited by 30 publications

(23 citation statements)

References 47 publications

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“…Second, the restraint imposed by p53 on glycolysis (see above) has indirect but consistent antioxidant consequences, which presumably originated by the need to control increased ROS generation by actively respiring mitochondria. Thus, p53-mediated transactivation of TIGAR and G6PD (12,131) and repression of PGM (100) cooperatively inhibit the glycolytic flow and at the same time stimulate the PPP, thereby increasing the generation of NADPH, which is required for proficient ROS scavenging by reduced glutathione.…”

Section: Anti-and Pro-oxidant Effects Of P53mentioning

confidence: 99%

Mitochondrial Liaisons of p53

Galluzzi

Morselli

Kepp

et al. 2011

Antioxidants & Redox Signaling

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Mitochondria play a central role in cell survival and cell death. While producing the bulk of intracellular ATP, mitochondrial respiration represents the most prominent source of harmful reactive oxygen species. Mitochondria participate in many anabolic pathways, including cholesterol and nucleotide biosynthesis, yet also control multiple biochemical cascades that contribute to the programmed demise of cells. The tumor suppressor protein p53 is best known for its ability to orchestrate a transcriptional response to stress that can have multiple outcomes, including cell cycle arrest and cell death. p53-mediated tumor suppression, however, also involves transcription-independent mechanisms. Cytoplasmic p53 can physically interact with members of the BCL-2 protein family, thereby promoting mitochondrial membrane permeabilization. Moreover, extranuclear p53 can suppress autophagy, a major prosurvival mechanism that is activated in response to multiple stress conditions. Thirty years have passed since its discovery, and p53 has been ascribed with an ever-increasing number of functions. For instance, p53 has turned out to influence the cell's redox status, by transactivating either anti- or pro-oxidant factors, and to regulate the metabolic switch between glycolysis and aerobic respiration. In this review, we will analyze the mechanisms by which p53 affects the balance between the vital and lethal functions of mitochondria.

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Section: Anti-and Pro-oxidant Effects Of P53mentioning

confidence: 99%

Mitochondrial Liaisons of p53

Galluzzi

Morselli

Kepp

et al. 2011

Antioxidants & Redox Signaling

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“…p53 serves as an energy inspector sensing the decrease of ATP levels and stimulating oxidative phosphorylation through upregulation of the synthesis of the cytochrome c oxidase 2 (SCO2) gene that encodes a copper chaperone protein required for the assembly of mitochondrial cytochrome c oxidase (complex IV) (7,8), as well as transcriptional activation of subunit I of cytochrome c oxidase (9). Furthermore, p53 activates TP53-induced glycolysis and the apoptosis regulator (TIGAR), which functions to direct glucose to the pentose phosphate pathway (PPP), as well as glucose-6-phosphate dehydrogenase (G6PD), a glycolytic enzyme that catalyzes a rate-limiting step in the PPP (10,11). The increase in PPP results in the stimulation of nucleotide synthesis and production of NADPH, which is an important component of the antioxidant defense system (12).…”

Section: Introductionmentioning

confidence: 99%

p53 protects lung cancer cells against metabolic stress

Sinthupibulyakit

Ittarat²,

Clair³

et al. 2010

Int J Oncol

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Abstract. The preferential use of aerobic glycolysis for energy production by cancer cells, a phenomenon known as the 'Warburg effect', is well recognized and is being considered for therapeutic applications. However, whether inhibition of glycolysis will be effective in all types of cancer is unclear. The current study shows that a glycolytic inhibitor, 2-deoxy-D-glucose (2DG), exhibits the cytotoxic effect on non-small cell lung cancer in a p53-dependent manner. 2DG significantly inhibits ATP production in p53-deficient lung cancer cells (H358) but not in p53-wt cells (A549). In contrast to p53-wt cells, p53-defective cells are unable to compensate for their need of energy via oxidative phosphorylation (OXPHOS) when glycolysis is inhibited. In the presence of p53, increased ROS from OXPHOS increases the expression of p53 target genes known to modulate metabolism, including synthesis of cytochrome c oxidase 2 (SCO2) and TP53-induced glycolysis and apoptosis regulator (TIGAR). Importantly, 2DG selectively induces the expression of the antioxidant enzymes manganese superoxide dismutase (MnSOD) and glutathione peroxidase 1 (GPx1) in a p53-dependent manner. The results demonstrate that the killing of cancer cells by the inhibitor of glycolysis is more efficient in cancer cells without functional p53 and that p53 protects against metabolic stress by up-regulation of oxidative phosphorylation and modulation of antioxidants.

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“…However, several laboratories have shown the association of the mammalian protein with chromatin and numerous studies used chromatin immunoprecipitation or similar assays to estimate a high number of p53 binding sites in mammalian genomes [27,28]. Recently, the physical association of human p53 with the elongating Pol II complex was demonstrated in Saccharomyces cerevisiae cells [6].…”

Section: Discussionmentioning

confidence: 99%

Misregulated RNA Pol II C-terminal domain phosphorylation results in apoptosis

Schauer

Tombácz²,

Ciurciu³

et al. 2009

Cell. Mol. Life Sci.

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Misregulation of the level of RNA polymerase II carboxyl-terminal domain (CTD) phosphatase, Fcp1, in Drosophila results in high level of caspase-mediated apoptosis. Apoptosis induction by Fcp1 misregulation requires the presence of Drosophila melanogaster (Dm)p53, but occurs without the transcriptional activation of Dmp53 proapoptotic targets rpr, ark, and hid. Overproduction of a transcription activation-defective mutant Dmp53 protein increases, while Dmp53 null background decreases significantly the level of apoptosis in Fcp1-misregulated animals. Generating the apoptotic signal does not require the function of the ATM and Rad3-related kinase (ATR), and no significant level of nucleo-cytoplasmic translocation of Dmp53 is detectable in cells expressing Fcp1 at an abnormal level. Immunostaining of larval salivary gland polytene chromosomes with anti-Dmp53 antibodies indicates Dmp53 localization at several transcriptionally active chromosomal regions in wild-type cells, while in Fcp-misregulated cells the association of Dmp53 with specific chromosomal sites is decreased.

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Discovery of novel tumor suppressor p53 response elements using information theory

Cited by 30 publications

References 47 publications

Mitochondrial Liaisons of p53

Mitochondrial Liaisons of p53

p53 protects lung cancer cells against metabolic stress

Misregulated RNA Pol II C-terminal domain phosphorylation results in apoptosis

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