Constitutive androstane receptor activation evokes the expression of glycolytic genes
Andrei A. YarushkinYuliya A. KazantsevaElena A. ProkopyevaDiana N. MarkovaYuliya A. PustylnyakVladimir O. Pustylnyak
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Constitutive androstane receptor
PKM2
PKM2
Warburg Effect
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Constitutive androstane receptor
PKM2
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Gluconeogenesis
Pyruvic acid
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Abstract Abiotic and biotic stresses cause significant yield losses in all crops. Acquisition of stress tolerance in plants requires rapid reprogramming of gene expression. SR1/CAMTA3, a member of signal responsive transcription factors (TFs), functions both as a positive and a negative regulator of biotic stress responses and as a positive regulator of cold stress-induced gene expression. Using high throughput RNA-seq, we identified ~3000 SR1-regulated genes. Promoters of about 60% of the differentially expressed genes have a known DNA binding site for SR1, suggesting that they are likely direct targets. Gene ontology analysis of SR1-regulated genes confirmed previously known functions of SR1 and uncovered a potential role for this TF in salt stress. Our results showed that SR1 mutant is more tolerant to salt stress than the wild type and complemented line. Improved tolerance of sr1 seedlings to salt is accompanied with the induction of salt-responsive genes. Furthermore, ChIP-PCR results showed that SR1 binds to promoters of several salt-responsive genes. These results suggest that SR1 acts as a negative regulator of salt tolerance by directly repressing the expression of salt-responsive genes. Overall, this study identified SR1-regulated genes globally and uncovered a previously uncharacterized role for SR1 in salt stress response.
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Activities of jejunal glycolytic enzymes were measured in 6 normal and 7 testosterone deficient men on controlled diets before and after testosterone. Jejunal glycolytic enzymes were measured in the hypogonadal males after isocaloric diets: glucose, fructose, and both together. In comparison with normals, the hypogonadal males showed significantly decreased activities of jejunal pyruvate kinase, fructose-1-phosphate aldolase and fructose diphosphate aldolase (p < 0.001) and no significant difference in hexokinase. Both normal and hypogonadal males showed significantly increased activity of pyruvate kinase after oral testosterone (10 mg/day for 2 days). Intramuscular testosterone increased the activity of pyruvate kinase in the hypogonadal males. Dietary changes produced less adaptive changes in jejunal glycolytic enzyme activities in hypogonadal males than in normal subjects. This lack of adaptive change may be related to testosterone deficiency. We conclude that testosterone-deficient adult males have decreased activities of certain jejunal glycolytic enzymes, which are increased by the administration of oral and intramuscular testosterone. Jejunal biopsy provides a useful means of studying the effect of hormones on human enzyme activities.
Hexokinase
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PKM2
Warburg Effect
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Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive interstitial lung disease of poor prognosis with a paucity of therapeutic options. Similarities between cancer cell biology and fibro-prolifortative pathomechanisms in fibrosis are becoming increasingly recognised, in particular the role of cell metabolism in driving these processes. Aims: A hallmark of certain tumours is their ability to anabolically fuel cell proliferation by aerobic glycolysis. Increased de novo expression of the glycolytic enzyme pyruvate kinase M2 (PKM2) central to this process, and targeting PKM2 with small molecules attenuates tumor cell proliferation and reduces tumorigenesis in animal models. We hypothesised aerobic glycolysis involving PKM2 may be important driving fibroblast proliferation. Methods: We investigated the role of PKM2 in supporting proliferation of primary human lung fibroblasts (HLF) in vitro, using the commercially available PKM2 activator TEPP-46 and the glucose analogue 2-deoxyglucose (2-DG) to dissect the metabolic demands of HLF during proliferation. Results: We show that PKM2 mRNA and protein is expressed in HLF. Treatment with the glucose analogue 2-Deoxy glucose or the PKM2 activator TEPP-46 significantly reduced HLF DNA synthesis over 72 hours in response to fetal calf serum or PDGF-stimulation, in a concentration-dependent manner. Conclusions: These data show that HLF express the key glycolytic enzyme PKM2 isoform, which can be targeted pharmacologically. Moreover, pharmacological manipulation of glucose metabolism indicates that glycolytic intermediates are critical for HLF proliferation.
PKM2
Anaerobic glycolysis
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SUMMARY Nervous system function relies on the establishment of complex gene expression programs that provide neuron-type-specific and core pan-neuronal features. These complementary regulatory paradigms are controlled by terminal selector and parallel-acting transcription factors (TFs), respectively. Here, we identify the Nuclear Factor Y (NF-Y) TF as a pervasive regulator of both neuron-type-specific and pan-neuronal gene expression. Mapping global NF-Y targets reveals direct binding to the cis -regulatory regions of pan-neuronal genes and terminal selector TFs. We show that NFYA-1 controls pan-neuronal gene expression directly through binding to CCAAT boxes in target gene promoters and indirectly by regulating the expression of terminal selector TFs. Further, we find that NFYA-1 regulation of neuronal gene expression is important for neuronal activity and motor function. Thus, our research sheds light on how global neuronal gene expression programs are buffered through direct and indirect regulatory mechanisms.
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Abstract Tumor cells express the glycolytic regulator pyruvate kinase subtype M2 (M2‐PK), which can occur in a tetrameric form with high affinity to its substrate phosphoenolpyruvate (PEP) and a dimeric form with a low PEP affinity. The transition between both conformations contributes to the control of glycolysis and is important for tumor cell proliferation and survival. Here we targeted M2‐PK by synthetic peptide aptamers, which specifically bind to M2‐PK and shift the isoenzyme into its low affinity dimeric conformation. The aptamer‐induced dimerization and inactivation of M2‐PK led to a significant decrease in the PK mass‐action ratio as well as ATP:ADP ratio in the target cells. Furthermore, the expression of M2‐PK‐binding peptide aptamers moderately reduced the growth of immortalized NIH3T3 cell populations by decelerating cell proliferation, but without affecting apoptotic cell death. Moreover, the M2‐PK‐binding peptide aptamers also reduced the proliferation rate of human U‐2 OS osteosarcoma cells. In the present study, we developed the first specific inhibitors of the pyruvate kinase isoenzyme type M2 and present evidence that these inhibitors moderately decelerate tumor cell proliferation. © 2008 Wiley‐Liss, Inc.
PKM2
Aptamer
Warburg Effect
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