Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons are known to have a lower glycolytic rate than astrocytes and when stressed they are unable to upregulate glycolysis because of low Pfkfb3 (6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3) activity. This enzyme generates fructose-2,6-bisphosphate (F2,6P(2)), the most potent activator of 6-phosphofructo-1-kinase (Pfk1; ref. 4), a master regulator of glycolysis. Here, we show that Pfkfb3 is absent from neurons in the brain cortex and that Pfkfb3 in neurons is constantly subject to proteasomal degradation by the action of the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1. By contrast, astrocytes have low APC/C-Cdh1 activity and therefore Pfkfb3 is present in these cells. Upregulation of Pfkfb3 by either inhibition of Cdh1 or overexpression of Pfkfb3 in neurons resulted in the activation of glycolysis. This, however, was accompanied by a marked decrease in the oxidation of glucose through the pentose phosphate pathway (a metabolic route involved in the regeneration of reduced glutathione) resulting in oxidative stress and apoptotic death. Thus, by actively downregulating glycolysis by APC/C-Cdh1, neurons use glucose to maintain their antioxidant status at the expense of its utilization for bioenergetic purposes.
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PMID:The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. 1944 25

Neurons are thought to be particularly vulnerable cells against reactive oxygen and nitrogen species (RONS) damage (nitrosative stress), due in part to their weak antioxidant defense and low ability to compensate energy homeostasis. Intriguingly, nitrosative stress efficiently stimulates the rate of the antioxidant pentose-phosphate pathway (PPP), which generates NADPH a necessary cofactor for the reduction of glutathione disulfide. In fact, inhibition of PPP sensitizes cultured neurons to glutathione oxidation and apoptotic death, whereas its stimulation confers resistance to nitrosative stress. Furthermore, we recently described that neurons can preferentially use glucose through the PPP by inhibiting glycolysis, which is achieved by continuously degrading the glycolytic positive-effector protein, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (Pfkfb3) by the action of the E3 ubiquitine ligase anaphase-promoting complex/cyclosome (APC/C)(Cdh1). These results suggest that the antioxidant fragility of neurons may be compensated by the PPP at the expense of inhibiting bioenergetic glycolysis.
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PMID:The pentose-phosphate pathway in neuronal survival against nitrosative stress. 1993 72

Following inhibition of mitochondrial respiration neurons die rapidly, whereas astrocytes utilize glycolytically-generated ATP to increase their mitochondrial membrane potential, thus becoming more resistant to pro-apoptotic stimuli. Neurons are unable to increase glycolysis due to the lack of activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, isoform 3 (PFKFB3). In neurons, PFKFB3 is degraded constantly via the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)- CDH1. Glucose metabolism in neurons is directed mainly to the pentose phosphate pathway, leading to regeneration of reduced glutathione. In addition to their relevance to brain physiology and pathophysiology, these observations suggest that APC/C-CDH1 might link activation of glycolysis and cell proliferation as it is also involved in the regulation of cell cycle proteins.
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PMID:Glycolysis: a bioenergetic or a survival pathway? 2000 13

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis by its ability to synthesize fructose-2,6-bisphosphate, a potent allosteric activator of 6-phosphofructo-1-kinase. Being a substrate of the E3 ubiquitin ligase anaphase-promoting complex-Cdh1 (APC(Cdh1)), PFKFB3 is targeted to proteasomal degradation in neurons. Here, we show that activation of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) stabilized PFKFB3 protein in cortical neurons. Expressed PFKFB3 was found to be mainly localized in the nucleus, where it is subjected to degradation; however, expression of PFKFB3 lacking the APC(Cdh1)-targeting KEN motif, or following NMDAR stimulation, promoted accumulation of PFKFB3 and its release from the nucleus to the cytosol through an excess Cdh1-inhibitable process. NMDAR-mediated increase in PFKFB3 yielded neurons having a higher glycolysis and lower pentose-phosphate pathway (PPP); this led to oxidative stress and apoptotic neuronal death that was counteracted by overexpressing glucose-6-phosphate dehydrogenase, the rate-limiting enzyme of the PPP. Furthermore, expression of the mutant form of PFKFB3 lacking the KEN motif was sufficient to trigger oxidative stress and apoptotic death of neurons. These results reveal that, by inhibition of APC(Cdh1), glutamate receptors activation stabilizes PFKFB3 thus switching neuronal metabolism leading to oxidative damage and neurodegeneration.
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PMID:Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. 2242 67

Recent advances in the field of brain energy metabolism strongly suggest that glutamate receptor-mediated neurotransmission is coupled with molecular signals that switch-on glucose utilization pathways to meet the high energetic requirements of neurons. Failure to adequately coordinate energy supply for neurotransmission ultimately results in a positive amplifying loop of receptor over-activation leading to neuronal death, a process known as excitotoxicity. In this review, we revisited current concepts in excitotoxic mechanisms, their involvement in energy substrate utilization, and the signaling pathways that coordinate both processes. In particular, we have focused on the novel role played by the E3 ubiquitin ligase, anaphase-promoting complex/cyclosome (APC/C)-Cdh1, in cell metabolism. Our laboratory identified 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) -a key glycolytic-promoting enzyme- as an APC/C-Cdh1 substrate. Interestingly, APC/C-Cdh1 activity is inhibited by over-activation of glutamate receptors through a Ca(2+)-mediated mechanism. Furthermore, by inhibiting APC/C-Cdh1 activity, glutamate-receptors activation promotes PFKFB3 stabilization, leading to increased glycolysis and decreased pentose-phosphate pathway activity. This causes a loss in neuronal ability to regenerate glutathione, triggering oxidative stress and delayed excitotoxicity. Further investigation is critical to identify novel molecules responsible for the coupling of energy metabolism with glutamatergic neurotransmission and excitotoxicity, as well as to help developing new therapeutic strategies against neurodegeneration.
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PMID:Brain energy metabolism in glutamate-receptor activation and excitotoxicity: role for APC/C-Cdh1 in the balance glycolysis/pentose phosphate pathway. 2341 42

Cdh1 is a regulatory subunit of the anaphase promoting complex/cyclosome (APC/C), known to be involved in regulating neuronal survival. The role of Cdh1 in volatile anesthetics-induced neuronal apoptosis in the developing brain is unknown. In this study, we used postnatal day 7 (P7) and day 21 (P21) mice exposed to 2.3% sevoflurane for 6 h to investigate at which age and duration of exposure sevoflurane affects the expression of Cdh1 and glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and that of the pentose phosphate pathway (PPP) enzyme, glucose-6-phosphate dehydrogenase (G6PD). Furthermore, we tested whether the cyclin-dependent kinases (cdks) inhibitor roscovatine could counteract the effects caused by exposure to sevoflurane. Finally, we applied the glycolysis inhibitor 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3-PO), G6PD inhibitor dehydroepiandrosterone (DHEA), and exogenous reduced glutathione to examine the contribution of the glycolysis pathway and PPP to sevoflurane-induced neuroapoptosis. We found that prolonged sevoflurane anesthesia significantly reduces the Cdh1 level in P7 mice compared to in the P21 ones; moreover, the decrease in Cdh1 level results in a switch in glucose metabolism from the PPP to neuronal glycolysis. This leads to an imbalance between reactive oxygen species production and reduced glutathione level in the developing brain, which is more susceptible to oxidative stress. As a result, sevoflurane induces neuroapoptosis through Cdh1-mediated glucose metabolism reprogramming. Our study demonstrates a critical role of Cdh1 in sevoflurane-induced neuroapoptosis by shifting PPP to the glycolytic pathway in the developing brain. These findings suggest that Cdh1 may be a novel target for preventing volatile anesthetics-induced neurotoxicity and memory impairment.
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PMID:Cdh1-Mediated Metabolic Switch from Pentose Phosphate Pathway to Glycolysis Contributes to Sevoflurane-Induced Neuronal Apoptosis in Developing Brain. 3074 26

Accumulation of nucleotide building blocks prior to and during S phase facilitates DNA duplication. Herein, we find that the anaphase-promoting complex/cyclosome (APC/C) synchronizes ribose-5-phosphate levels and DNA synthesis during the cell cycle. In late G1 and S phases, transketolase-like 1 (TKTL1) is overexpressed and forms stable TKTL1-transketolase heterodimers that accumulate ribose-5-phosphate. This accumulation occurs by asymmetric production of ribose-5-phosphate from the non-oxidative pentose phosphate pathway and prevention of ribose-5-phosphate removal by depleting transketolase homodimers. In the G2 and M phases after DNA synthesis, expression of the APC/C adaptor CDH1 allows APC/CCDH1 to degrade D-box-containing TKTL1, abrogating ribose-5-phosphate accumulation by TKTL1. TKTL1-overexpressing cancer cells exhibit elevated ribose-5-phosphate levels. The low CDH1 or high TKTL1-induced accumulation of ribose-5-phosphate facilitates nucleotide and DNA synthesis as well as cell cycle progression in a ribose-5-phosphate-saturable manner. Here we reveal that the cell cycle control machinery regulates DNA synthesis by mediating ribose-5-phosphate sufficiency.
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PMID:APC/CCDH1 synchronizes ribose-5-phosphate levels and DNA synthesis to cell cycle progression. 3117 80

Reprogramming of glucose metabolism is a key event in tumorigenesis and progression. Here, we show that active c-Src stimulates glycolysis by phosphorylating (Tyr194) and activating PFKFB3, a key enzyme that boosts glycolysis by producing fructose-2,6-bisphosphate and activating PFK1. Increased glycolysis intermediates replenish non-oxidative pentose phosphate pathway (PPP) and serine pathway for biosynthesis of cancer cells. PFKFB3 knockout (KO) cells and their counterpart reconstituted with PFKFB3-Y194F show comparably impaired abilities for proliferation, migration, and xenograft formation. Furthermore, PFKFB3-Y194F knockin mice show impaired glycolysis and, mating of these mice with APCmin/+ mice attenuates spontaneous colon cancer formation in APCmin/+ mice. In summary, we identify a specific mechanism by which c-Src mediates glucose metabolism to meet cancer cells' requirements for maximal biosynthesis and proliferation. The PFKFB3-Tyr194 phosphorylation level highly correlates with c-Src activity in clinical tumor samples, indicating its potential as an evaluation for tumor prognosis.
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PMID:c-Src Promotes Tumorigenesis and Tumor Progression by Activating PFKFB3. 3220 81