NF-κB: Regulation by Methylation

In normal cells exposed to stress, the central transcription factor NF-κB is activated only transiently, to modulate the activation of downstream immune responses. However, in most cancers, NF-κB is abnormally activated constitutively, contributing thus to oncogenesis and tumor progression. Therefore, downregulating NF-κB activity is an important goal of cancer treatment. In order to control NF-κB activity therapeutically, it is helpful to understand the molecular mechanisms that normally govern its activation and how dysregulated NF-κB activity may aid the development of disease. Recent evidence from our laboratories and others indicates that, in addition to various posttranslational modifications of NF-κB that have been observed previously, including phosphorylation, ubiquitination, and acetylation, NF-κB can be methylated reversibly on lysine or arginine residues by histone-modifying enzymes, including lysine and arginine methyl transferases and demethylases. Furthermore, these methylations are required to activate many downstream genes. Interestingly, amplifications and mutations of several such enzymes have been linked to cancer. We propose that some of these mutations may alter the methylation not only of histones but also of NF-κB, making them attractive therapeutic targets

The control of interferon-inducible gene expression

AbstractThe αβ interferons (IFNs) transiently induce genes through an IFN-stimulable DNA response element (ISRE). IFN-cell surface receptor interaction triggers the cytoplasmic activation of the complex primary transcription factor E, which on translocation and interaction with the ISRE initiates transcription. Whether E is activated directly through the receptor(s) or through a more classical second message pathway(s) and the roles of additional factors in the αβ and γ IFN responses remain to be established. Meanwhile analysis of mutants has revealed complexity and overlap in the α,β and γ IFN response pathways and the products of at least two viruses have been shown to inhibit IFN-inducible gene expression

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis.

Copper levels are known to be elevated in inflamed and malignant tissues. But the mechanism underlying this selective enrichment has been elusive. In this study, we report a axis by which inflammatory cytokines, such as IL-17, drive cellular copper uptake via the induction of a metalloreductase, STEAP4. IL-17-induced elevated intracellular copper level leads to the activation of an E3-ligase, XIAP, which potentiates IL-17-induced NFκB activation and suppresses the caspase 3 activity. Importantly, this IL-17-induced STEAP4-dependent cellular copper uptake is critical for colon tumor formation in a murine model of colitis-associated tumorigenesis and STEAP4 expression correlates with IL-17 level and XIAP activation in human colon cancer. In summary, this study reveals a IL-17-STEAP4-XIAP axis through which the inflammatory response induces copper uptake, promoting colon tumorigenesis

Weighing black holes with warm absorbers

We present a new technique for determining an upper limit for the mass of the black hole in active galactic nuclei showing warm absorption features. The method relies on the balance of radiative and gravitational forces acting on outflowing warm absorber clouds. It has been applied to 6 objects: five Seyfert 1 galaxies: IC 4329a, MCG-6-30-15, NGC 3516, NGC 4051 and NGC 5548; and one radio-quiet quasar: MR 2251-178. We discuss our result in comparison with other methods. The procedure could also be applied to any other radiatively driven optically thin outflow in which the spectral band covering the major absorption is directly observed.Comment: 13 pages, 6 figures, 7 tables. MNRAS accepte

Microcystin aids in cold temperature acclimation: Differences between a toxic Microcystis wildtype and non-toxic mutant

For Microcystis aeruginosa PCC 7806, temperature decreases from 26 °C to 19 °C double the microcystin quota per cell during growth in continuous culture. Here we tested whether this increase in microcystin provided M. aeruginosa PCC 7806 with a fitness advantage during colder-temperature growth by comparing cell concentration, cellular physiology, reactive oxygen species damage, and the transcriptomics-inferred metabolism to a non-toxigenic mutant strain M. aeruginosa PCC 7806 ΔmcyB. Photo-physiological data combined with transcriptomic data revealed metabolic changes in the mutant strain during growth at 19 °C, which included increased electron sinks and non-photochemical quenching. Increased gene expression was observed for a glutathione-dependent peroxiredoxin during cold treatment, suggesting compensatory mechanisms to defend against reactive oxygen species are employed in the absence of microcystin in the mutant. Our observations highlight the potential selective advantages of a longer-term defensive strategy in management of oxidative stress (i.e., making microcystin) vs the shorter-term proactive strategy of producing cellular components to actively dissipate or degrade oxidative stress agents

Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1

Signal transducer and activator of transcription 1 (STAT1) plays a pivotal role in the innate immune system by directing the transcriptional response to interferons (IFNs). STAT1 is activated by Janus kinase (JAK)‐mediated phosphorylation of Y701. To determine whether STAT1 contributes to cellular responses without this phosphorylation event, we generated mice with Y701 mutated to a phenylalanine (Stat1(Y701F)). We show that heterozygous mice do not exhibit a dominant‐negative phenotype. Homozygous Stat1(Y701F) mice show a profound reduction in Stat1 expression, highlighting an important role for basal IFN‐dependent signaling. The rapid transcriptional response to type I IFN (IFN‐I) and type II IFN (IFNγ) was absent in Stat1(Y701F) cells. Intriguingly, STAT1Y701F suppresses the delayed expression of IFN‐I‐stimulated genes (ISG) observed in Stat1(−/−) cells, mediated by the STAT2/IRF9 complex. Thus, Stat1(Y701F) macrophages are more susceptible to Legionella pneumophila infection than Stat1(−/−) macrophages. Listeria monocytogenes grew less robustly in Stat1(Y701F) macrophages and mice compared to Stat1(−/−) counterparts, but STAT1Y701F is not sufficient to rescue the animals. Our studies are consistent with a potential contribution of Y701‐unphosphorylated STAT1 to innate antibacterial immunity

A ROSAT HRI survey of bright nearby galaxies

We use the extensive public archive of ROSAT High Resolution Imager (HRI) observations to carry out a statistical investigation of the X-ray properties of nearby galaxies. Specifically we focus on the sample of 486 bright (B_T < 12.5) northern galaxies studied by Ho, Filippenko and Sargent (HFS) in the context of their exploration of the optical spectroscopic properties of nearby galactic nuclei. Over 20% of HFS galaxies are encompassed in ROSAT HRI fields of reasonable (> 10ks) exposure. The X-ray sources detected within the optical extent of each galaxy are categorised as either nuclear or non-nuclear depending on whether the source is positioned within or outside of a 25 arcsecond radius circle centred on the optical nucleus. A nuclear X-ray source is detected in over 70% of the galaxies harbouring either a Seyfert or LINER nucleus compared to a detection rate of only ~40% in less active systems. The correlation of the H alpha luminosity with nuclear X-ray luminosity previously observed in QSOs and bright Seyfert 1 galaxies appears to extend down into the regime of ultra-low luminosity (L(x)~10^38 - 10^40 erg/s) active galactic nuclei (AGN). The inferred accretion rates for this sample of low-luminosity AGN are significantly sub-Eddington. In total 142 non-nuclear sources were detected. In combination with published data for M31 this leads to a luminosity distribution (normalised to an optical blue luminosity of L(B) = 10^10 L(solar)) for the discrete X-ray source population in spiral galaxies of the form dN/dL38 = 1.0 +/- 0.2 L38^-1.8, where L38 is the X-ray luminosity in units of 10^38 erg/s. The implied L(x)/L(B) ratio is ~1.1 x 10^39 erg/s/(10^10 L(solar)). The nature of the substantial number of ``super-luminous'' non-nuclear objects detected in the survey is discussed.Comment: 20 pages, 7 figures, accepted for publication in MNRAS. Also available from http://www.star.le.ac.uk/~tro/papers/xhfs.p

Sunyaev-Zel'dovich Cluster Profiles Measured with the South Pole Telescope

We present Sunyaev-Zel'dovich measurements of 15 massive X-ray selected galaxy clusters obtained with the South Pole Telescope. The Sunyaev-Zel'dovich (SZ) cluster signals are measured at 150 GHz, and concurrent 220 GHz data are used to reduce astrophysical contamination. Radial profiles are computed using a technique that takes into account the effects of the beams and filtering. In several clusters, significant SZ decrements are detected out to a substantial fraction of the virial radius. The profiles are fit to the beta model and to a generalized NFW pressure profile, and are scaled and stacked to probe their average behavior. We find model parameters that are consistent with previous studies: beta=0.86 and r_core/r_500 = 0.20 for the beta model, and (alpha, beta, gamma, c_500)=(1.0,5.5,0.5,1.0) for the generalized NFW model. Both models fit the SPT data comparably well, and both are consistent with the average SZ profile out to the virial radius. The integrated Compton-y parameter Y_SZ is computed for each cluster using both model-dependent and model-independent techniques, and the results are compared to X-ray estimates of cluster parameters. We find that Y_SZ scales with Y_X and gas mass with low scatter. Since these observables have been found to scale with total mass, our results point to a tight mass-observable relation for the SPT cluster survey.Comment: 21 pages, 24 figures, updated to published versio

A Comparison of Maps and Power Spectra Determined from South Pole Telescope and Planck Data

We study the consistency of 150 GHz data from the South Pole Telescope (SPT) and 143 GHz data from the Planck satellite over the patch of sky covered by the SPT-SZ survey. We first visually compare the maps and find that the residuals appear consistent with noise after accounting for differences in angular resolution and filtering. We then calculate (1) the cross-spectrum between two independent halves of SPT data, (2) the cross-spectrum between two independent halves of Planck data, and (3) the cross-spectrum between SPT and Planck data. We find the three cross-spectra are well-fit (PTE = 0.30) by the null hypothesis in which both experiments have measured the same sky map up to a single free calibration parameter---i.e., we find no evidence for systematic errors in either data set. As a by-product, we improve the precision of the SPT calibration by nearly an order of magnitude, from 2.6% to 0.3% in power. Finally, we compare all three cross-spectra to the full-sky Planck power spectrum and find marginal evidence for differences between the power spectra from the SPT-SZ footprint and the full sky. We model these differences as a power law in spherical harmonic multipole number. The best-fit value of this tilt is consistent among the three cross-spectra in the SPT-SZ footprint, implying that the source of this tilt is a sample variance fluctuation in the SPT-SZ region relative to the full sky. The consistency of cosmological parameters derived from these datasets is discussed in a companion paper.Comment: 15 pages, 9 figures. Published in The Astrophysical Journal. Current arxiv version matches published versio