Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The glucose/insulin response element of the L-pyruvate kinase gene is a perfect palindrome located from nt -168 to -144 with respect to the cap site. This element (L4) is partially homologous to MLTF binding sites. Its full efficiency requires cooperation with a contiguous binding site for HNF4, termed L3 and located from nt -145 to -125. In the presence of the L4 element contiguous to L3, cyclic AMP inhibits activity of the L-PK promoter while in its absence, or when the normal L4-L3 contiguity is modified, cyclic AMP behaves as a transcriptional activator that does not seem to be sequence-specific. Therefore, we propose that the mechanism of inhibition of the L-PK gene by cyclic AMP requires precise interactions between the nucleoprotein complex built up at sites L4 and L3 and other components of the L-PK transcription initiation complex.
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PMID:Cis-regulation of the L-type pyruvate kinase gene promoter by glucose, insulin and cyclic AMP. 131 61

Hepatocytes isolated from adult fasted rats and cultured in the presence of thyroid hormones, glucocorticoids, and in a serum-free medium conserve the essentials of their differentiated function and hormonal sensitivity for at least 1 week. In these cells, the gene for L-type pyruvate kinase is expressed only when glucose and insulin are present together, each of them being inactive by itself. Inhibition of the expression of the L-type pyruvate kinase gene which occurs when glucose and/or insulin are removed from the culture medium is not associated with accumulation of the phosphoenolpyruvate carboxykinase mRNA, which argues against the involvement of intracellular cyclic AMP in this phenomenon. Rather, a transcriptional activator, derived from carbohydrate metabolism and accumulating in the presence of insulin, seems to be needed to support the expression of the L-type pyruvate kinase gene. Glucagon, in vitro as in vivo, inhibits production of the L-type pyruvate kinase mRNAs. In addition to their roles on the production of these mRNAs, glucose and insulin on the one hand and glucagon on the other have profound effects on the stability of the L-type pyruvate kinase messengers: the half-life of the mRNA whose production has been blocked by actinomycin D is 1 h in the presence of glucagon and 24 h in the presence of glucose and insulin. Glucagon and glucose/insulin partially antagonize each other's effect on mRNA stability.
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PMID:Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. 254 75

The grapevine is the natural host of the tumorigenic bacterium Agrobacterium vitis. Most of the A. vitis isolates can use tartrate, an unusually abundant compound in grapevine. The nopaline strain, AB4, contains a 170-kb conjugative plasmid (pTrAB4) encoding tartrate utilization. A 5.65-kb pTrAB4 region which enables non-tartrate-utilizing Agrobacterium tumefaciens to grow on tartrate was sequenced and mutagenized with the transcriptional fusion transposon Tn5-uidA1. This DNA fragment contains four intact open reading frames (ORFs) (ttuABCD) required for tartrate-dependent growth. The mutant phenotypes of each ORF, their homologies to published sequences, and their induction patterns allowed us to propose a model for tartrate utilization in A. vitis. ttuA encodes a LysR-like transcriptional activator and is transcribed in the absence of tartrate. ttuB codes for a protein with homology to transporter proteins and is required for entry of tartrate into bacteria. ttuC codes for a tartrate dehydrogenase, while ttuD lacks homology to known sequences; the growth properties of ttuD mutants suggest that TtuD catalyzes the second step in tartrate degradation. A fifth incomplete ORF (ttuE) encodes a pyruvate kinase which is induced by tartrate and required for optimal growth. Although the ttuABCD fragment allows growth of A. tumefaciens on tartrate, it does not provide full tartrate utilization in the original A. vitis background.
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PMID:Sequence and mutational analysis of a tartrate utilization operon from Agrobacterium vitis. 759 29

The INS-r3-GK27 insulinoma cells are endowed with artificially inducible glucokinase under control of the reverse tetracycline-dependent transcriptional activator. Moderate induction of glucokinase has been shown to result in proportionate increases in glycolytic flux and in potentiation of glucose effects on insulin secretion and pyruvate kinase gene expression. In cells with 20-fold overexpression of glucokinase, however, glucose activation of secretion and gene expression was severely impaired. Measurements of the glycolytic flux in cells with 7- and 21-fold increases in glucokinase activity and determination of the flux control coefficient of this enzyme showed that control of glycolysis at the glucokinase step was lost in the cells at the higher level of overexpression. Challenging the cells with glucose above 6 mM resulted in massive accumulation of glucose 6-phosphate and caused a rapid and sustained depletion of cellular ATP, in contrast with the glucose-induced rise in ATP in cells with wild-type glucokinase levels. Loss of cell viability ensued upon prolonged culture in high glucose. In summary, in insulinoma beta cells strongly overexpressing glucokinase, an imbalance between glucose phosphorylation and turnover of glucose 6-phosphate resulted in acute glucose intolerance due to trapping of cellular orthophosphate in dead-end product and severe paralysis of energy metabolism.
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PMID:Acute glucose intolerance in insulinoma cells with unbalanced overexpression of glucokinase. 932 99

Glucose-regulated transcription of the L-type pyruvate kinase (L-PK) gene is mediated through its glucose response element (GlRE/L4 box) composed of two degenerated E-boxes. Upstream stimulatory factor (USF) is a component of the transcriptional glucose response complex built up on the GlRE. Cooperation of the GlRE with the contiguous binding site (L3 box) for the orphan nuclear receptor hepatocyte nuclear factor 4 (HNF4) has also been suggested. We compared by transient transfection assays the effects of USF2a and other basic helix-loop-helix leucine zipper (bHLH-LZ) factors (TFE3, c-Myc, SREBP/ADD1) on the activity and glucose responsiveness of a minimal L-PK promoter directed by oligomerized glucose response units (L4L3 boxes). We found that: (i) although USF2a is intrinsically a moderate transcriptional activator, it has a strong stimulatory effect on the activity of the L4L3-based reporter construct in hepatocyte-derived cells and interferes with the glucose responsiveness; (ii) despite its potent ability as a transactivator, TFE3 alone is barely active on the GlRE in hepatocyte-derived cells; (iii) TFE3 as USF2a acts synergistically with HNF4 and abolishes glucose responsiveness of the promoter when overexpressed; (iv) in contrast, overexpression of HNF4 alone stimulates activity of the promoter without interfering with glucose responsiveness; (v) SREBP/ADD1 has a very weak activity on the L4L3 elements, only detectable in the presence of HNF4, and c-Myc does not interact with the GIRE of the L-PK promoter. Our studies indicate that different bHLH-LZ transcription factors known to recognize CACGTG-type E-boxes are not equivalent in acting through the L-PK glucose response element, with USF proteins being especially efficient in hepatocyte-derived cells.
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PMID:Effect of different basic helix-loop-helix leucine zipper factors on the glucose response unit of the L-type pyruvate kinase gene. 969 82

The transcriptional regulator GntR1 downregulates the genes for gluconate catabolism and pentose phosphate pathway in Corynebacterium glutamicum. Gluconate lowers the DNA binding affinity of GntR1, which is probably the mechanism of gluconate-dependent induction of these genes. In addition, GntR1 positively regulates ptsG, a gene encoding a major glucose transporter, and pck, a gene encoding phosphoenolpyruvate carboxykinase. Here, we searched for the new target of GntR1 on a genome-wide scale by chromatin immunoprecipitation in conjunction with microarray (ChIP-chip) analysis. This analysis identified 56 in vivo GntR1 binding sites, of which 7 sites were previously reported. The newly identified GntR1 sites include the upstream regions of carbon metabolism genes such as pyk, maeB, gapB, and icd, encoding pyruvate kinase, malic enzyme, glyceraldehyde 3-phosphate dehydrogenase B, and isocitrate dehydrogenase, respectively. Binding of GntR1 to the promoter region of these genes was confirmed by electrophoretic mobility shift assay. The activity of the icd, gapB, and maeB promoters was reduced by the mutation at the GntR1 binding site, in contrast to the pyk promoter activity, which was increased, indicating that GntR1 is a transcriptional activator of icd, gapB, and maeB and is a repressor of pyk. Thus, it is likely that GntR1 stimulates glucose uptake by inducing the phosphoenolpyruvate (PEP):carbohydrate phosphotransferase system (PTS) gene while repressing pyk to increase PEP availability in the absence of gluconate. Repression of zwf and gnd may reduce the NADPH supply, which may be compensated by the induction of maeB and icd. Upregulation of icd, gapB, and maeB and downregulation of pyk by GntR1 probably support gluconeogenesis.
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PMID:Genome-wide analysis of the role of global transcriptional regulator GntR1 in Corynebacterium glutamicum. 2498 7

Therapy based on targeted inhibition of BCR-ABL tyrosine kinase has greatly improved the prognosis for patients with Philadelphia chromosome (Ph)-positive leukemia and tyrosine kinase inhibitors (TKI) have become standard therapy. However, some patients acquire resistance to TKI that is frequently associated with point mutations in BCR-ABL. We previously reported that a medium-chain fatty-acid derivative AIC-47 induced transcriptional suppression of BCR-ABL and perturbation of the Warburg effect, leading to growth inhibition in Ph-positive leukemia cells. Herein, we showed that AIC-47 had anti-leukemic effects in either wild type (WT)- or mutated-BCR-ABL-harboring cells. AIC-47 suppressed transcription of BCR-ABL gene regardless of the mutation through downregulation of transcriptional activator, c-Myc. Reprogramming of the metabolic pathway has been reported to be associated with resistance to anti-cancer drugs; however, we found that a point mutation of BCR-ABL was independent of the profile of pyruvate kinase muscle (PKM) isoform expression. Even in T315I-mutated cells, AIC-47 induced switching of the expression profile of PKM isoforms from PKM2 to PKM1, suggesting that AIC-47 disrupted the Warburg effect. In a leukemic mouse model, AIC-47 greatly suppressed the increase in BCR-ABL mRNA level and improved hepatosplenomegaly regardless of the BCR-ABL mutation. Notably, the improvement of splenomegaly by AIC-47 was remarkable and might be equal to or greater than that of TKI. These findings suggest that AIC-47 might be a promising agent for overcoming the resistance of Ph-positive leukemia to therapy.
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PMID:Potent antiproliferative effect of fatty-acid derivative AIC-47 on leukemic mice harboring BCR-ABL mutation. 3054 79

Pancreatic ductal adenocarcinoma is one of the deadliest malignant tumors, and many genes play important roles in its development. The hepatocyte nuclear factor-1a (HNF-1a) gene encodes HNF-1a, which is a transcriptional activator. HNF-1a regulates the tissue-specific expression of multiple genes, especially in pancreatic islet cells and in the liver. However, the role of the HNF-1a gene in the development of pancreatic cancer is still unclear. Here, we used immunohistochemical staining and real-time PCR to analyze HNF-1a expression in pancreatic cancer tissue. Stable cell lines with HNF-1a knockdown or overexpression were established to analyze the role of HNF-1a in pancreatic cancer cell proliferation and apoptosis by colony formation assay and flow cytometry. We also analyzed the L-type pyruvate kinase (PKLR) promoter sequence to identify the regulatory effect of HNF-1a on PKLR transcription and confirmed the HNF-1a binding site in the PKLR promoter via a chromatin immunoprecipitation assay. HNF-1a was found to be overexpressed in pancreatic cancer and promoted proliferation while inhibiting apoptosis in pancreatic cancer cells. PKLR was identified as the downstream target gene of HNF-1a and binding of HNF-1a at two sites in PKLR (-1931/-1926 and -966/-961) regulated PKLR transcription. In conclusion, HNF-1a is overexpressed in pancreatic cancer, and the transcription factor HNF-1a can promote pancreatic cancer growth and apoptosis resistance via its target gene PKLR.
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PMID:HNF-1a promotes pancreatic cancer growth and apoptosis resistance via its target gene PKLR. 3207 80