Protein kinase A-mediated CREB phosphorylation is an oxidant-induced survival pathway in alveolar type II cells

Oxidant stress plays a role in the pathogenesis of pulmonary diseases, including fibrotic lung disease and cancer. We previously found that hydrogen peroxide (H2O2) initiates an increase in Ca2+/cAMP-response element binding protein (CREB) phosphorylation in C10 alveolar type II cells that requires activation of extracellular regulated kinases 1/2 (ERK1/2). Here, we investigated the role of crosstalk between protein kinase A (PKA) and epidermal growth factor receptor (EGFR) in oxidant-induced signaling to ERK1/2 and CREB in C10 cells. Application of H2O2 increased nuclear accumulation of PKA, and inhibition of PKA with H89 reduced oxidant-mediated phosphorylation of both CREB and ERK1/2. Single cell measurements of cAMP and redox status, using a FRET-based biosensor and a redox-sensitive GFP, respectively, indicated that H2O2 increases production of cAMP that correlates with redox state. Inhibition of EGFR activity decreased both H2O2-induced CREB phosphorylation and translocation of PKA to the nucleus, suggesting that crosstalk between PKA and EGFR underlies the oxidant-induced CREB response. Furthermore, knockdown of CREB expression using siRNA led to a decrease in bcl-2 and an increase in oxidant-induced apoptosis. Together these data reveal a novel role for crosstalk between PKA, ERK1/2 and CREB that mediates cell survival during oxidant stress

Novel Data Fusion Method and Exploration of Multiple Information Sources for Transcription Factor Target Gene Prediction

Background. Revealing protein-DNA interactions is a key problem in understanding transcriptional regulation at mechanistic level. Computational methods have an important role in predicting transcription factor target gene genomewide. Multiple data fusion provides a natural way to improve transcription factor target gene predictions because sequence specificities alone are not sufficient to accurately predict transcription factor binding sites. Methods. Here we develop a new data fusion method to combine multiple genome-level data sources and study the extent to which DNA duplex stability and nucleosome positioning information, either alone or in combination with other data sources, can improve the prediction of transcription factor target gene. Results. Results on a carefully constructed test set of verified binding sites in mouse genome demonstrate that our new multiple data fusion method can reduce false positive rates, and that DNA duplex stability and nucleosome occupation data can improve the accuracy of transcription factor target gene predictions, especially when combined with other genome-level data sources. Cross-validation and other randomization tests confirm the predictive performance of our method. Our results also show that nonredundant data sources provide the most efficient data fusion.Peer reviewe

The Radio to GeV Afterglow of GRB 221009A

GRB 221009A (z = 0.151) is one of the closest known long γ-ray bursts (GRBs). Its extreme brightness across all electromagnetic wavelengths provides an unprecedented opportunity to study a member of this still-mysterious class of transients in exquisite detail. We present multiwavelength observations of this extraordinary event, spanning 15 orders of magnitude in photon energy from radio to γ-rays. We find that the data can be partially explained by a forward shock (FS) from a highly collimated relativistic jet interacting with a low-density, wind-like medium. Under this model, the jet’s beaming-corrected kinetic energy (E K ∼ 4 × 1050 erg) is typical for the GRB population. The radio and millimeter data provide strong limiting constraints on the FS model, but require the presence of an additional emission component. From equipartition arguments, we find that the radio emission is likely produced by a small amount of mass (≲6 × 10−7 M ⊙) moving relativistically (Γ ≳ 9) with a large kinetic energy (≳1049 erg). However, the temporal evolution of this component does not follow prescriptions for synchrotron radiation from a single power-law distribution of electrons (e.g., in a reverse shock or two-component jet), or a thermal-electron population, perhaps suggesting that one of the standard assumptions of afterglow theory is violated. GRB 221009A will likely remain detectable with radio telescopes for years to come, providing a valuable opportunity to track the full lifecycle of a powerful relativistic jet