Cross-talk between aryl hydrocarbon receptor and the inflammatory response: a role for nuclear factor-κB.

The aryl hydrocarbon receptor (AhR) is involved in the regulation of immune responses, T-cell differentiation, and immunity. Here, we show that inflammatory stimuli such as LPS induce the expression of AhR in human dendritic cells (DC) associated with an AhR-dependent increase of CYP1A1 (cytochrome P4501A1). In vivo data confirmed the elevated expression of AhR by LPS and the LPS-enhanced 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated induction of CYP1A1 in thymus of B6 mice.

EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization.

Crystallographic studies have offered understanding of how receptor tyrosine kinases from the ErbB family are regulated by their growth factor ligands. A conformational change of the EGFR (ErbB1) was shown to occur upon ligand binding, where a solely ligand-mediated mode of dimerization/activation was documented. However, this dogma of dimerization/activation was revolutionized by the discovery of constitutively active ligand-independent EGFR mutants.

Cigarette smoke exposure causes changes in Scavenger Receptor B1 level and distribution in lung cells.

Scavenger Receptor B1 has been shown to play a prominent role in the uptake and delivery of vitamin E from HDL and is likely involved in regulating vitamin E in the lung. We have previously demonstrated that lung Scavenger Receptor B1 levels (protein and mRNA) are modulated by cigarette smoke in mice and this was accompanied by changes in lung vitamin E. To further characterize the molecular mechanism(s) involved in this process, human alveolar epithelial cells were exposed to cigarette smoke and Scavenger Receptor B1 cellular levels and distribution were assessed.

Monte Carlo simulation of cell death signaling predicts large cell-to-cell stochastic fluctuations through the type 2 pathway of apoptosis.

Apoptosis, or genetically programmed cell death, is a crucial cellular process that maintains the balance between life and death in cells. The precise molecular mechanism of apoptosis signaling and the manner in which type 1 and type 2 pathways of the apoptosis signaling network are differentially activated under distinct apoptotic stimuli is poorly understood. Based on Monte Carlo stochastic simulations, we show that the type 1 pathway becomes activated under strong apoptotic stimuli, whereas the type 2 mitochondrial pathway dominates apoptotic signaling in response to a weak death signal.

Epidermal growth factor receptor exposed to cigarette smoke is aberrantly activated and undergoes perinuclear trafficking.

Exposure to hydrogen peroxide (H2O2), one of the reactive oxidants in the gas phase of cigarette smoke (CS), induces aberrant phosphorylation of the epidermal growth factor receptor (EGFR), resulting in the lack of ubiquitination by c-Cbl, and impaired degradation. EGFR activation without the feedback regulation of normal degradation leads to uncontrolled cell growth and tumor promotion. Using immunoprecipitation, immunoblotting, and confocal microscopy, we now demonstrate that the pattern of EGFR activation by CS is similar to H2O2.

Epidermal growth factor receptor exposed to oxidative stress undergoes Src- and caveolin-1-dependent perinuclear trafficking.

The epidermal growth factor (EGF) receptor (EGFR) has been found to be overexpressed in several types of cancer cells, and the regulation of its oncogenic potential has been widely studied. The paradigm for EGFR down-regulation involves the trafficking of activated receptor molecules from the plasma membrane, through clathrin-coated pits, and into the cell for lysosomal degradation. We have previously shown that oxidative stress generated by H2O2 results in aberrant phosphorylation of the EGFR.

Life and death decisions: ceramide generation and EGF receptor trafficking are modulated by oxidative stress.

Reactive oxidants are associated with the pathogenesis of pulmonary diseases and affect various cell functions, from proliferation to apoptosis. We have shown that oxidants exert growth control on airway epithelial cells by modulating upstream receptor function. Additionally, hydrogen peroxide-mediated oxidative stress modulates ceramide levels to induce apoptosis in lung epithelium.

c-Cbl-mediated ubiquitinylation is required for epidermal growth factor receptor exit from the early endosomes.

Epidermal growth factor receptor (EGFR) controls cell growth and has a key role in tumorigenic processes. The extent of EGFR signaling is tightly regulated by post-transcriptional modifications leading to down-regulation of the levels of the receptor. Previous studies from our laboratory demonstrated that the reactive oxidant hydrogen peroxide activates the EGFR, yet, without down-regulation of the receptor levels, which results in prolonged receptor signaling.