The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.

https://www.zora.uzh.ch/id/eprint/1285/1/Wenger2005-3MaV.pdf

Integration of Oxygen Signaling at the Consensus HRE

Sleep is a complex behavioral state that occupies one-third of the human life span. Although viewed as a passive condition, sleep is a highly active and dynamic process. The sleep-related decrease ...

Disorders of glucose metabolism in sleep apnea

Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired’ to oncogenic mechanisms driving cancer.

/pdf/hypoxia-signaling-pathways-in-cancer-metabolism-the-149g4qpsxh.pdf

Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways.

Most tumor cells show different metabolic pathways than normal cells. Even under the conditions of sufficient oxygen, they produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, which is known as aerobic glycolysis or the Warburg effect. Lung cancer is a malignant tumor with one of the highest incidence and mortality rates in the world at present. However, the exact mechanisms underlying lung cancer development remain unclear. The three key enzymes of glycolysis are hexokinase, phosphofructokinase, and pyruvate kinase. Lactate dehydrogenase catalyzes the transfer of pyruvate to lactate. All four enzymes have been reported to be overexpressed in tumors, including lung cancer, and can be regulated by many oncoproteins to promote tumor proliferation, migration, and metastasis with dependence or independence of glycolysis. The discovery of aerobic glycolysis in the 1920s has provided new means and potential therapeutic targets for lung cancer.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1759-7714.12148

Review of aerobic glycolysis and its key enzymes – new targets for lung cancer therapy

The increased glucose metabolism in cancer cells is required to fulfill their high energetic and biosynthetic demands. Changes in the metabolic activity of cancer cells are caused by the activation of oncogenes or loss of tumor suppressors. They can also be part of the metabolic adaptations to the conditions imposed by the tumor microenvironment, such as the hypoxia response. Among the metabolic enzymes that are modulated by these factors are the 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases (PFKFBs), a family of bifunctional enzymes that control the levels of fructose 2,6-bisphosphate (Fru-2,6-P2). This metabolite is important for the dynamic regulation of glycolytic flux by allosterically activating the rate-limiting enzyme of glycolysis phosphofructokinase-1 (PFK-1). Therapeutic strategies designed to alter the levels of this metabolite are likely to interfere with the metabolic balance of cancer cells, and could lead to a reduction in cancer cell proliferation, invasiveness and survival. This article will review our current understanding of the role of PFKFB proteins in the control of cancer metabolism and discuss the emerging interest in these enzymes as potential targets for the development of antineoplastic agents.

/pdf/balancing-glycolytic-flux-the-role-of-6-phosphofructo-2-xu9o0yj4vu.pdf

Balancing glycolytic flux: the role of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatases in cancer metabolism.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.febslet.2004.08.053

Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1α activation

The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) is a family of bifunctional enzymes which is responsible for maintaining the cellular levels of fructose-2,6-bisphosphate, a powerful allosteric activator of glycolysis. Here we report the overexpression of PFKFB-1, -2, -3 and -4 mRNA in the human lung cancers when compared with corresponding normal tissues counterparts as well as PFKFB-4 and -3 protein levels. The lung carcinoma cell line A549, under conditions of normal oxygen tension, has also shown increased transcript levels of PFKFB-2, -3 and -4 when compared to normal tissues. Moreover, hypoxia highly induced the expression of PFKFB-2, PFKFB-3 and especially PFKFB-4 isozymes are highly induced in the lung carcinoma cells. Thus, our results' clearly demonstrated overexpression of PFKFB gene family isozymes in the lung cancers and they possible role in the Warburg effect.

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family overexpression in human lung tumor.

PROBLEM TO BE SOLVED: To obtain a gas sampling apparatus for continuously bringing a target constituent in a gas sample into contact with an absorption liquid for high concentration, and to provide an on-site type high-precision analysis system, where the gas sampling apparatus and a portable detection apparatus are combined. SOLUTION: A required amount of gas sample that is sucked by an air pump 2 through an air filter 1 is discharged to a nebulizer 4 by a gas flowmeter 3. The absorption liquid 6 that is supplied by a liquid dispense pump 5 and is atomized in a minute liquid drop shape by gas samples by the nebulizer flows on the inner wall of a denuder tube 7 and on the surface of a filler along with the gas sample by repeating contact, and a target constituent is condensed and captured in the absorption liquid. Then, the gas sample and the absorption liquid reach a gas-liquid separation cylinder 8 for inertia separation. The absorption liquid for condensing and capturing the target substitute is recovered as a measuring sample solution 9 of a target constituent detection apparatus, and the remaining gas sample is exhausted. The target constituent that is condensed and captured by the absorption liquid is detected by the detection apparatus. A series of analysis operation of the condensation capturing and detection of the target constituent is performed continuously. COPYRIGHT: (C)2004,JPO&NCIPI

Continuous concentrated gas sampling apparatus by nebulizer-denuder interlocking, and gas analysis apparatus incorporating the gas sampling apparatus and analysis method

PROBLEM TO BE SOLVED: To provide an anti-Neisseria bacterium composition which can sterilize Neisseria bacterium in oral cavities and is safe and simple. SOLUTION: Tea powder or tea extract contains one or more substances selected from the group consisting of (+)-catechin, (-)-epicatechin, (+)- gallocatechin, (-)-epigallocatechin, (-)-catechin gallate, (-)-epicatechin gallate, (-)-gallocatechin gallate, (-)-epigallocatechin gallate, free theaflavin, theaflavin monogallate A, theaflavin monogallate B and theaflavin digallate. A composition containing the substance exhibits a strong antibacterial action against Neisseria bacterium which is one of bacteria in oral cavities. COPYRIGHT: (C)2003,JPO

Anti-neissria bacterium composition

The modulation by dietary fat levels of intestine carcinogenesis is well documented New developments suggest that calcium ions may also play a role A rapid bioassay, the induction of foci of aberrant crypts in the colon, was used to explore the interaction between dietary fat and calcium Male F344 rats 6 weeks of age were placed on diets containing 5 or 20% corn oil, and 004 or 032% calcium ion, as calcium lactate Each dietary group was fed 400 ppm 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and negative controls received the diets alone A positive control group was given 2 mg A/-nitrosomethylurea (NMU) intrarectally four times in a 2-week period All rats were killed after 9 weeks The intestinal tract was rinsed with Krebs-Ringer buffer After staining a 6-cm segment of the descending colon and rectum with 02% methylene blue, foci of aberrant crypts were evaluated microscopically With PhIP as a carcinogen, the rats on a high-fat, low-calcium level had more foci of aberrant crypts than animals on a low-fat level With the higher calcium level, there were fewer foci and aberrant crypts, but the effect of fat was still significant With NMU and a low-calcium level, the effect of fat level was evident However, with the higher calcium intake, there were considerably more foci of aberrant crypts than on the low-calcium level, and the effect of the dietary fat level was not obvious Thus, with the dietary carcinogen PhIP, an enhancing effect of high fat intake and a protective effect of a higher calcium intake on the induction of intestinal foci of aberrant crypts could be visualized in a 9-week test With limited intrarectal administration of NMU, the association with dietary fat was evident on a low-calcium intake On a high-calcium intake, there was a considerably higher number of aberrant crypt foci, perhaps because of the more advanced carcinogenic process with NMU ?Environ Health Perspect 102(Suppl 6):53-55 (1994)

Hiroyasu Esumi

Papers

Hypoxia induces transcription of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 gene via hypoxia-inducible factor-1α activation

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family overexpression in human lung tumor.

Continuous concentrated gas sampling apparatus by nebulizer-denuder interlocking, and gas analysis apparatus incorporating the gas sampling apparatus and analysis method

Anti-neissria bacterium composition

The Role of Fat and Calcium in the Production of Foci of Aberrant Crypts in the Colon of Rats Fed 2-Amino-1-methyl-6^