Harmonic oscillator model of the insulin and IGF1 receptors' allosteric binding and activation

The insulin and insulin-like growth factor 1 receptors activate overlapping signalling pathways that are critical for growth, metabolism, survival and longevity. Their mechanism of ligand binding and activation displays complex allosteric properties, which no mathematical model has been able to account for. Modelling these receptors' binding and activation in terms of interactions between the molecular components is problematical due to many unknown biochemical and structural details. Moreover, substantial combinatorial complexity originating from multivalent ligand binding further complicates the problem. On the basis of the available structural and biochemical information, we develop a physically plausible model of the receptor binding and activation, which is based on the concept of a harmonic oscillator. Modelling a network of interactions among all possible receptor intermediaries arising in the context of the model (35, for the insulin receptor) accurately reproduces for the first time all the kinetic properties of the receptor, and provides unique and robust estimates of the kinetic parameters. The harmonic oscillator model may be adaptable for many other dimeric/dimerizing receptor tyrosine kinases, cytokine receptors and G-protein-coupled receptors where ligand crosslinking occurs

Gene expression profiles of post-Chernobyl thyroid cancers.

PURPOSE OF REVIEW: We discuss new evidence supporting the existence of a susceptibility to develop cancer following radiation exposure that is variable in the general population and could be measurable from gene expression. RECENT FINDINGS: Microarray analysis of spontaneous and post-Chernobyl thyroid cancers has uncovered gene expression radiation signatures, one of which could be related to the putative cause of these tumors and to a DNA repair pathway. A gene expression signature distinguishes the lymphocytes drawn from parents of children with retinoblastoma and the lymphocytes of parents of healthy children. The first are more radiosensitive. A familial clustering pattern is observed in radiation-induced meningiomas. SUMMARY: The existence of a susceptibility to develop radiation-induced cancer would explain why only a minority of the population most heavily exposed to radiation following the Chernobyl disaster developed a cancer. The possibility of measuring this susceptibility from gene expression has a number of implications for research, medicine and radioprotection.Journal ArticleResearch Support, Non-U.S. Gov'tReviewinfo:eu-repo/semantics/publishe

Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ.

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H(2)O(2)) is still controversial. In this work, we studied whether the high levels of H(2)O(2) produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H(2)O(2) (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs ( approximately 2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H(2)O(2)-induced DNA damage. Moreover, we showed that DNA breaks induced by H(2)O(2) were more slowly repaired than those induced by irradiation. In conclusion, H(2)O(2) causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H(2)O(2) in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Additional file 4: Figure S5. of Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots

Observed abundance of all sRNA subtypes at the three different time points, columns represent different participants. (TIFF 218 kb