Loss of p53 enhances catalytic activity of IKKβ through O-linked β-N-acetyl glucosamine modification

Kawauchi, Keiko; Araki, Keigo; Tobiume, Kei; Tanaka, Nobuyuki

doi:10.1073/pnas.0813210106

Cited by 172 publications

(156 citation statements)

References 34 publications

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“…In addition to the established role of p53 in cell cycle arrest and apoptosis, recent evidence has demonstrated that p53 reduces glycolytic flux and increases oxidative phosphorylation, halting the Warburg effect. [137][138][139][140][141][142][143] TIGAR (Tp53-induced glycolysis and apoptosis regulator) was identified to function as a fructose-2,6-bisphosphatase (Fru-2,6-BP), antagonizing the third step of glycolysis and thereby redirecting metabolite flux to the pentose phosphate pathway. [138][139][140] Interestingly, basal or low levels of p53 expression have been suggested to provide antioxidant effects and thus elicit cellular protection rather than cell death.…”

Section: Other Modulation Of Mitohk-iimentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

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Section: Other Modulation Of Mitohk-iimentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

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“…In addition, NF-κB has also been shown to have a role in cellular transformation and tumorigenesis by upregulating the expression of some antiapoptosis genes upon inflammatory cytokine stimulation (14,15). The effect of NF-κB on tumorigenesis, however, is strongly modulated by the p53 tumor suppressor, which can antagonize NF-κB activity (16)(17)(18). In p53-null background, the NF-κB signaling pathway has been shown to promote cell proliferation through NF-κB-mediated transcription of antiapoptotic factors and thus promote tumor growth (18).…”

Section: Resultsmentioning

confidence: 99%

Regulation of apoptosis by the circadian clock through NF-κB signaling

Lee

Sancar

2011

Proc. Natl. Acad. Sci. U.S.A.

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In mice and humans the circadian rhythm of many biochemical reactions, physiology, and behavior is generated by a transcriptionaltranslation feedback loop (TTFL) made up of the so-called core clock genes/proteins. The circadian system interfaces with most signaling pathways including those involved in cell proliferation and inflammation. Cryptochrome (CRY) is a core clock protein that plays an essential role in the repressive arm of the TTFL. It was recently reported that mutation of CRY in p53-null mice delayed the onset of cancer. It was therefore suggested that CRY mutation may activate p53-independent apoptosis pathways, which eliminate premalignant and malignant cells and thus delay overt tumor formation. Here we show that CRY mutation sensitizes p53 mutant and oncogenically transformed cells to tumor necrosis factor α (TNFα)-initiated apoptosis by interfacing with the NF-κB signaling pathway through the GSK3β kinase and alleviating prosurvival NF-κB signaling. These findings provide a mechanistic foundation for the delayed onset of tumorigenesis in clock-disrupted p53 mutant mice and suggest unique therapeutic strategies for treating cancers associated with p53 mutation. hepatocellular carcinoma | inflammatory cytokine | extrinsic apoptotic pathway T he circadian rhythm in mammalian organisms is generated by a molecular clock comprising four gene/protein groups (1-5): The CLOCK (NPAS2) and BMAL1 transactivators and the cryptochrome 1 and 2 (CRY1/2) and the period 1 and 2 (PER1/ 2) repressors. CLOCK (or NPAS2) and BMAL1 make heterodimers, which act on the promoters of CRY1/2 and PER1/2 and activate their transcription. The CRY and PER proteins in turn, after a time delay of ill-defined mechanism, inhibit the CLOCK-BMAL1 transactivator and hence their own transcription to close the TTFL. This core TTFL directly or indirectly affects most cellular functions, and as a result, clock disruption by core clock gene mutation is expected to have serious repercussions at the cellular and organismal levels.We recently reported that mice of the p53 −/− Cry1 −/− Cry −/− (hereafter p53 KO Cry DKO ) genotype exhibited delayed onset of spontaneous cancer relative to p53 −/− (p53 KO ) mice (6). When analyzed for their response to genotoxic stress, it was found that p53 KO Cry DKO cells were more sensitive to UV-induced apoptosis than p53 KO cells even though they are identical in terms of DNA repair and DNA damage checkpoint functions (6). Therefore, we ascribed the reduced clonogenic survival of p53 KO Cry DKO cells upon UV irradiation, relative to p53 KO cells, to enhanced p53-independent apoptosis as a consequence of CRY mutation. We also suggested that the delayed onset of cancer and prolonged lifespan of mice of p53 KO Cry DKO genotype may have been caused by enhanced apoptosis of oncogenically transformed cells before giving rise to macroscopic tumors (6). In line with these findings we recently determined that p53 KO Cry DKO tumors are more responsive to oxaliplatin than p53 KO tumors (7). However, UV and oxaliplatin...

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“…As O-GlcNAc levels rise in response to elevated UDP-GlcNAc, increased cancer cell HBP flux may be expected to drive hyper-O-GlcNAcylation. In support of this, loss of the p53 tumor suppressor in mouse embryonic fibroblasts increases the rate of aerobic glycolysis, Glut3 expression (24), and HBP flux and leads to elevation of O-GlcNAcylation (25). Cancer cells are also addicted to glutamine (26).…”

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confidence: 99%

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

Vosseller

2014

Journal of Biological Chemistry

173

145

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O-Linked ␤-N-acetylglucosamine (O-GlcNAc) is a carbohydrate post-translational modification on hydroxyl groups of serine and/or threonine residues of cytosolic and nuclear proteins. Analogous to phosphorylation, O-GlcNAcylation plays crucial regulatory roles in cellular signaling. Recent work indicates that increased O-GlcNAcylation is a general feature of cancer and contributes to transformed phenotypes. In this minireview, we discuss how hyper-O-GlcNAcylation may be linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics. We also discuss potential therapeutic modulation of O-GlcNAc levels in cancer treatment.

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Loss of p53 enhances catalytic activity of IKKβ through O-linked β-N-acetyl glucosamine modification

Cited by 172 publications

References 34 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Regulation of apoptosis by the circadian clock through NF-κB signaling

Cancer Metabolism and Elevated O-GlcNAc in Oncogenic Signaling

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