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Oxidative stress from excess H 2 O 2 activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H 2 O 2 , it is unclear whether they are activated at the same H 2 O 2 concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H 2 O 2 activate p53, NRF2 and JUN. Yet under high H 2 O 2 , these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H 2 O 2 is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated. H 2 O 2 stress is known to activate a slew of transcription factors that restore redox balance. Here, the authors use live-cell imaging and single-cell analysis to reveal that the transcription factors that are activated and their timing of activation is dose dependent.

Recently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of “alternating access” like those exporters, cycling through inward-open, occluded, and outward-open conformations. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies on all the major conformations. To shed light on this, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP-Vi) at a 3.1 Å resolution determined by cryo-electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of the nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the “screwdriver” action at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.

Natural Killer (NK) cells can target and destroy cancer cells, yet tumor microenvironments typically suppress NK cell recruitment and cytotoxicity. The epidermal growth factor receptor (EGFR) is a potent oncogene that can activate survival, migration, and proliferation pathways, and clinical data suggests it may also play an immunomodulating role in cancers. Recent work has demonstrated a novel role for nuclear EGFR (nEGFR) in regulating transcriptional events unique from the kinase domain. Using a novel peptide therapeutic (cSNX1.3) that inhibits retrograde trafficking of EGFR and an EGFR nuclear localization mutant, we discovered that nEGFR suppresses NK cell recruitment and cytotoxicity. RNA-Seq analysis of breast cancer cells treated with cSNX1.3 or modified to lack a nuclear localization sequence (EGFR ΔNLS ) revealed the EGF-dependent induction of NK activating receptor ligands, while kinase inhibition by erlotinib did not impact these genes. NanoString analysis of tumor-bearing WAP-TGFα transgenic mice treated with cSNX1.3 demonstrated an increase in immune cell populations and activating genes. Additionally, immunohistochemistry confirmed an increase in NK cells upon cSNX1.3 treatment. Finally, cSNX1.3 treatment was found to enhance NK cell recruitment and cytotoxicity in vitro. Together, the data demonstrate a unique immunomodulatory role for nEGFR.

Oxidative stress from excess H O activates transcription factors that restore redox balance and repair oxidative damage. Although many transcription factors are activated by H O , it is unclear whether they are activated at the same H O concentration, or time. Dose-dependent activation is likely as oxidative stress is not a singular state and exhibits dose-dependent outcomes including cell-cycle arrest and cell death. Here, we show that transcription factor activation is both dose-dependent and coordinated over time. Low levels of H O activate p53, NRF2 and JUN. Yet under high H O , these transcription factors are repressed, and FOXO1, NF-κB, and NFAT1 are activated. Time-lapse imaging revealed that the order in which these two groups of transcription factors are activated depends on whether H O is administered acutely by bolus addition, or continuously through the glucose oxidase enzyme. Finally, we provide evidence that 2-Cys peroxiredoxins control which group of transcription factors are activated.

Hydrogen Peroxide (H O ) stress activates transcription factors (TFs) in a dose-dependent manner, with distinct TFs activated in response to low versus high H O . Here, we show that high H O imposes a translational constraint that prevents accumulation of TFs requiring protein synthesis. Under low H O conditions, TFs including p53, NRF2, and ATF4, accumulate and drive stress-responsive gene expression. In contrast, high H O induces coordinated inhibition of translation initiation and elongation through activation of the integrated stress response (ISR), suppression of mTORC1 signaling, and activation of eEF2K, thereby blocking accumulation of these TFs. Inhibition of translation and repression of p53, NRF2, and ATF4 coincides with nuclear shuttling of pre-existing TFs, including FOXO1, NFAT1, and NF-κB. We propose that shuttling TFs provide a backup mechanism to respond to severe oxidative stress while translation is inhibited. Together, these findings identify translational control as a central switch governing transcription factor response to H O stress.

Recently, several ATP-binding cassette (ABC) importers have been found to adopt the typical fold of type IV ABC exporters. Presumably, these importers would function under the transport scheme of “alternating access” like those exporters: cycling through conformations of inward-open, occluded, and outward-open. Understanding how the exporter-like importers move substrates in the opposite direction requires structural studies in all the major conformations. To shed light on that, here we report the structure of yersiniabactin importer YbtPQ from uropathogenic Escherichia coli in the occluded conformation trapped by ADP-vanadate (ADP.Vi) at 3.1Å resolution determined by cryo electron microscopy. The structure shows unusual local rearrangements in multiple helices and loops in its transmembrane domains (TMDs). In addition, the dimerization of nucleotide-binding domains (NBDs) promoted by the vanadate trapping is highlighted by the “screwdriver” action happening at one of the two hinge points. These structural observations are rare and thus provide valuable information to understand the structural plasticity of the exporter-like ABC importers.

This paper describes the establishment of the Australasian College of Chiropractors. The President of the Chiropractors’ Association of Australia (National) Limited, Dr Dennis Richards, is scheduled to announce the formation of the College at the annual general meeting of the company in October 2006. The National Board of the CAA has led an extensive process to investigate and develop a submission to establish a professional college for chiropractors in Australasia. The Board approved the principle of the College early in 2005 and established a sub-committee of the Board as the College Management Committee (CMC). The Board recognises that the continued development of the chiropractic profession is more than ever contingent on the very real need to foster a culture of research and scholarship that would support professional development and sees the College as a proactive step in this direction. This paper documents the process of establishing the College and explains its purpose, governance and membership categories.