Background High doses of ionizing radiation result in biological damage; however,

Background High doses of ionizing radiation result in biological damage; however, the precise relationships between long-term health effects, including cancer, and low-dose exposures remain poorly understood and are currently extrapolated using high-dose exposure data. known roles in radiation responses including TP53BP1 as well as previously unidentified radiation-responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatic analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role for MAP kinase Solcitinib manufacture and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conclusions Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provide a basis for the systems-level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low-dose radiation exposure on human health. Introduction Humans are continuously exposed to low doses of ionizing radiation from both environmental (radon and cosmic rays) and manmade (nuclear power plants and medical procedures) sources, and the health impacts from these exposures are still not well understood[1]. Exposure to these low doses of ionizing radiation could account for some of the frequent malignancies that develop and also other undesirable health effects. Several studies have recorded the consequences Rptor of high-dose rays exposure on human being health and determined lots of the root molecular systems that result in mutations, cancer advancement Solcitinib manufacture and loss of life [2]. A central problem of rays research is to comprehend whether the natural pathways associated with health results induced by high rays dosages behave inside a non-linear or linear way at low dosages. Implicit with this challenge may be the have to understand the root systems that govern the entire response of regular tissues Solcitinib manufacture subjected to low-dose rays. Oftentimes, the consequences of low-dose publicity are extrapolated from higher dosage research to assess potential health threats because of having less obtainable data on low-dose results[3]. Emerging proof, however, shows that the natural reactions to low- and high-dose exposures could be considerably different, as evidenced by modified proteins and gene manifestation information[4], [5], altered proteins post-translational adjustments (PTMs)[6], and findings that cancer risks from low-dose exposure may be overestimated[7]. These investigations show that extrapolation from high-dose experiments may not adequately reflect the low-dose response and point to the need for new studies to explore this issue. Biological systems are more complex than defined by the genome due in large part to the presence of PTMs that regulate protein activity. Known PTMs on proteins such as histone H2A.X, CHK2, ATM, and p53 undergo very robust changes in response to high doses of radiation compared to changes in protein levels. Phosphorylation, one of the most important and best characterized PTMs[8], is essential in signal transduction, Solcitinib manufacture gene regulation, and metabolic control in cells, especially in response to intracellular and extracellular changes and stimuli. Therefore, identification of phosphoproteins, specific phosphorylation sites that Solcitinib manufacture regulate protein function, and upstream signaling kinases will provide valuable insight into the molecular mechanisms that regulate the cellular responses to ionizing radiation. While traditional methods (e.g., immunohistochemistry) typically allow characterization of one phosphoprotein (often only one specific phosphorylation site) at a time, recent advancements in LC-MS technology now enable the broad proteome-wide study of phosphorylation (phosphoproteomics)[9], [10], [11], [12], [13] and enable identification of thousands of phosphorylations sites (and often multiple sites in an individual protein) in a particular proteome. Applying a data analysis pipeline specifically designed to facilitate phosphoproteomics analyses[14], we analyzed.

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