A comprehensive modular map of molecular interactions in RB/E2F pathway

We present, here, a detailed and curated map of molecular interactions taking place in the regulation of the cell cycle by the retinoblastoma protein (RB/RB1). Deregulations and/or mutations in this pathway are observed in most human cancers. The map was created using Systems Biology Graphical Notation language with the help of CellDesigner 3.5 software and converted into BioPAX 2.0 pathway description format. In the current state the map contains 78 proteins, 176 genes, 99 protein complexes, 208 distinct chemical species and 165 chemical reactions. Overall, the map recapitulates biological facts from approximately 350 publications annotated in the diagram. The network contains more details about RB/E2F interaction network than existing large-scale pathway databases. Structural analysis of the interaction network revealed a modular organization of the network, which was used to elaborate a more summarized, higher-level representation of RB/E2F network. The simplification of complex networks opens the road for creating realistic computational models of this regulatory pathway

A quantitative model for the evaluation of dose rates effects following exposure to low-dose gamma-radiation

Simultaneous consideration of the irradiation time and the cumulative dose is necessary for evaluating the risk of long-term exposure to radiation at low dose. This study intends to examine several numerical relationships between doses and dose rates in biological responses to gamma radiation. Data on inhibition of [3H] thymidine uptake and micronucleus formation in human osteosarcoma cells were analyzed using the median effective dose (MED) as a measure of the risk. MEDs were calculated using parameters estimated by fitting general logistic curves to the dose-response relationships for each group defined by irradiation time. Both biological responses, the inhibition of [3H] thymidine uptake and micronucleus formation, decreased sharply when the dose rates were less than 0.01 Gy/h. Exponential functions were fitted to the log relationships between MEDs and dose rates. This modified exponential model described well the quantitative effect of dose rates on MEDs, and suggested that risk is extremely low at very low dose rates

Apoptosis is observed in mesothelial cells after exposure to crocidolite asbestos

Asbestos causes protracted, dose-dependent increases in steady-state mRNA levels of the proto-oncogenes c-fos and c-jun, and AP-l DNA-binding activity in normal rat pleural mesothelial (RPM) cells (I). To determine the phenotypic end points of overexpression of these early response genes by asbestos, both cell proliferation and apoptosis were examined in confluent RPM cells exposed to a range of concentrations (1.25 to 10 p.g/cm' dish) of crocidolite asbestos for 24 and 48 h. Quantitation of RPM cells pulsed with 5-bromo-2'-deoxyuridine revealed that asbestos caused dose-dependent decreases in cells undergoing DNA synthesis. Decreases in cell proliferation were accompanied by dose-related increases in apoptosis using (l) terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (i.e., ApopTag technique), (2) 4',6-diamidino-2-phenylindole cell staining, and (3) fluorescent-activated cell sorter after incorporation of propidium iodide. Less striking but significant dose-related increases in apoptosis were observed in RPM cells exposed to H20, (300 p.M), and no apoptosis was seen after exposure of cells to high concentrations (10 p.g/cm' dish) of glass beads. Our results are unique in that they demonstrate that asbestos induces apoptosis in mesothelial cells at concentrations eliciting increased expression of the proto-oncogenes c-fos and c-jun