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BackgroundHypoxia-inducible expression of the erythropoietin (EPO) gene is mediated principally by hypoxia-inducible factor 2alpha (HIF-2alpha) in Hep3B cells under physiologic conditions. How/whether p300/CBP and the members of p160 coactivator family potentiate hypoxic induction of endogenous EPO and other HIF-2alpha and hypoxia-inducible factor 1alpha (HIF-1alpha) target genes remains unclear.Methodology/principal findingsWe demonstrate, using chromatin immunoprecipitation (ChIP) analysis, that the histone acetyl transferase (HAT) coactivators p300, SRC-1 and SRC-3 are recruited to the 3' enhancer of the EPO gene upon hypoxic stimulation, and that each associates with the enhancer in a periodic fashion. Hypoxia induced acetylation of the EPO gene 5' promoter at histone 4 and lysine 23 of histone 3. Knocking down SRC-3, but not SRC-1 or SRC-2, using short interfering RNAs (siRNAs), reduced EPO transcriptional activity. Knocking down p300 resulted in dramatic down-regulation of hypoxic stimulation of EPO gene transcription, negated recruitment of RNA polymerase II to the gene's promoter, and eliminated hypoxia-stimulated acetylation at the promoter and recruitments of SRC-1 and SRC-3 to the enhancer. The inhibitory effects of knocking down p300 and the chromatin remodeling coactivator, Brm/Brg-1, on EPO transcription were additive, suggesting that p300 and Brm/Brg-1 act independently. p300 was also required for hypoxia induced transcription of the HIF-1alpha target gene, VEGF, but was dispensable for induction of two other HIF-1alpha target genes, PGK and LDHA. Knocking down CBP, a homolog of p300, augmented hypoxic induction of VEGF, LDHA and PGK. Different HIF target genes also exhibited different requirements for members of the p160 coactivator family.Conclusions/significancep300 plays a central coactivator role in hypoxic induction of EPO. The coactivators exhibit different specificities for different HIF target genes and each can behave differently in transcriptional regulation of different target genes mediated by the same transcription factor.

CXCR4 is a chemokine receptor frequently overexpressed on primary tumor cells. Organs to which these cancers metastasize secrete CXCL12, the unique ligand for CXCR4, which stimulates invasion and metastasis to these sites. Similar to our previous work with the chemoprotective phytochemical, 3,3'-diindolylmethane (DIM), we show here that genistein also downregulates CXCR4 and CXCL12 and subsequently lowers the migratory and invasive potentials of breast and ovarian cancer cells. Moreover, genistein and DIM elicit a significantly greater cumulative effect in lowering CXCR4 and CXCL12 levels than either compound alone. Our data suggest a novel mechanism for the protective effects of phytochemicals against cancer progression and indicate that in combination, these compounds may prove even more efficacious.

The aromatic hydrocarbon receptor (AhR) mediates biological responses to certain exogenous ligands, such as the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and has also been demonstrated to modulate the cell cycle and differentiated state of several cell lines independently of exogenous ligands. In this study, we used DNA microarray analysis to elucidate the profile of genes responsive to the expression of unliganded AhR by re-introducing AhR into an AhR-deficient mouse derivative (c19) of the mouse hepatoma cell line Hepa 1c1c7. 22 gene products were up-regulated and 8 were down-regulated two-fold or more in c19 cells infected with a retroviral vector expressing mouse AhR. Surprisingly, expression of genes involved in cell proliferation or differentiation were not affected by introduction of AhR. AhR also did not restore expression of the albumin gene in c19 cells. Introduction of AhR into c12, a similar AhR-defective mouse hepatoma cell line, also did not restore albumin expression, and furthermore, did not lead to changes in cellular morphology or cell cycle parameters. These observations fail to support the notion that unliganded AhR regulates proliferation and differentiation of liver-derived cells.

Comprehensive Summary: Realizing the hydrogen economy by water electrolysis is an attractive approach for hydrogen production, while the efficient and stable bifunctional catalysts under high current densities are the bottleneck that limits the half‐cell reactions of water splitting. Here, we propose an approach of hydrothermal and thermal annealing methods for robust MoO2/MoNi4@Ru/RuO2 heterogeneous cuboid array electrocatalyst with multiplying surface‐active sites by depositing a monolayer amount of Ru. Benefiting from abundant MoO2/MoNi4@Ru/RuO2 heterointerfaces, MoO2/MoNi4@Ru/RuO2 heterogeneous cuboid array electrocatalysts effectively drive the alkaline water splitting with superior hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) performances. The synthesized MoO2/MoNi4@Ru/RuO2 has high HER activity, which realizes the working overpotentials of 48 mV at 50 mA·cm–2, further achieving overpotentials of 230 mV for industry‐level 1000 mA·cm–2 in alkaline water electrolysis. Moreover, it also showed an enhanced OER activity than commercial RuO2 with a small overpotential of 280 mV at 200 mA·cm–2 in alkaline media. When building an electrolyzer with electrodes of (–)MoO2/MoNi4@Ru/RuO2IIMoO2/ MoNi4@Ru/RuO2 (+), a cell voltage of 1.63 V and 1.75 V is just required to support the current density of 200 mA·cm–2 and 500 mA·cm–2 in alkaline water electrolysis, much lower than that of the electrolyzer of (–)Pt/CIIRuO2(+). This work demonstrates that MoO2/MoNi4@Ru/RuO2 heterogeneous nanosheet arrays are promising candidates for industrial water electrolysis applications, providing a possibility for the exploration of water electrolysis with a large current density. [ABSTRACT FROM AUTHOR]