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Dynamics of cellular responses to radiation.

ABSTRACT: Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radioresistance (IRR). With radioadaptive responses, low dose exposure can protect against subsequent challenges, and two mechanisms have been suggested: an intracellular mechanism, inducing cellular changes as a result of the priming radiation, and induction of a protected state by inter-cellular communication. We use mathematical models to examine the effect of these mechanisms on cellular responses to low dose radiation. We find that the intracellular mechanism can account for the occurrence of radioadaptive responses. Interestingly, the same mechanism can also explain the existence of the HRS and IRR phenomena, and successfully describe experimentally observed dose-response relationships for a variety of cell types. This indicates that different, seemingly unrelated, low dose phenomena might be connected and driven by common core processes. With respect to the inter-cellular communication mechanism, we find that it can also account for the occurrence of radioadaptive responses, indicating redundancy in this respect. The model, however, also suggests that the communication mechanism can be vital for the long term survival of cell populations that are continuously exposed to relatively low levels of radiation, which cannot be achieved with the intracellular mechanism in our model. Experimental tests to address our model predictions are proposed.

SUBMITTER: Wodarz D

PROVIDER: S-EPMC3983039 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Dynamics of cellular responses to radiation.

Wodarz Dominik D Sorace Ron R Komarova Natalia L NL

PLoS computational biology 20140410 4

Understanding the consequences of exposure to low dose ionizing radiation is an important public health concern. While the risk of low dose radiation has been estimated by extrapolation from data at higher doses according to the linear non-threshold model, it has become clear that cellular responses can be very different at low compared to high radiation doses. Important phenomena in this respect include radioadaptive responses as well as low-dose hyper-radiosensitivity (HRS) and increased radio ...[more]

PMID: 24722167

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Project description:Nuclear factor (NF)-?B is a transcription factor that plays significant role in immunity, cellular survival and inhibition of apoptosis, through the induction of genetic networks. Depending on the stimulus and the cell type, the members of NF-?B related family (RelA, c-Rel, RelB, p50, and p52), forms different combinations of homo and hetero-dimers. The activated complexes (Es) translocate into the nucleus and bind to the 10bp ?B site of promoter region of target genes in stimulus specific manner. In response to radiation, NF-?B is known to reduce cell death by promoting the expression of anti-apoptotic proteins and activation of cellular antioxidant defense system. Constitutive activation of NF-?B associated genes in tumour cells are known to enhance radiation resistance, whereas deletion in mice results in hypersensitivity to IR-induced GI damage. NF-?B is also known to regulate the production of a wide variety of cytokines and chemokines, which contribute in enhancing cell proliferation and tissue regeneration in various organs, such as the GI crypts stem cells, bone marrow etc., following exposure to IR. Several other cytokines are also known to exert potent pro-inflammatory effects that may contribute to the increase of tissue damage following exposure to ionizing radiation. Till date there are a series of molecules or group of compounds that have been evaluated for their radio-protective potential, and very few have reached clinical trials. The failure or less success of identified agents in humans could be due to their reduced radiation protection efficacy. In this review we have considered activation of NF-?B as a potential marker in screening of radiation countermeasure agents (RCAs) and cellular radiation responses. Moreover, we have also focused on associated mechanisms of activation of NF-?B signaling and their specified family member activation with respect to stimuli. Furthermore, we have categorized their regulated gene expressions and their function in radiation response or modulation. In addition, we have discussed some recently developed radiation countermeasures in relation to NF-?B activation.

Dataset Information

Dynamics of cellular responses to radiation.

Publications

Dynamics of cellular responses to radiation.

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