Analysing the Role of UVB-Induced Translational Inhibition and PP2Ac Deactivation in NF-κB Signalling Using a Minimal Mathematical Model
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{"title"=>"Analysing the role of UVB-induced translational inhibition and PP2Ac deactivation in NF-κB signalling using a minimal mathematical model", "type"=>"journal", "authors"=>[{"first_name"=>"Johannes", "last_name"=>"Witt", "scopus_author_id"=>"56684470100"}, {"first_name"=>"Fabian", "last_name"=>"Konrath", "scopus_author_id"=>"55316861900"}, {"first_name"=>"Oliver", "last_name"=>"Sawodny", "scopus_author_id"=>"6603314950"}, {"first_name"=>"Michael", "last_name"=>"Ederer", "scopus_author_id"=>"16068089700"}, {"first_name"=>"Dagmar", "last_name"=>"Kulms", "scopus_author_id"=>"6602771318"}, {"first_name"=>"Thomas", "last_name"=>"Sauter", "scopus_author_id"=>"7004204514"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22815735", "sgr"=>"84864015449", "doi"=>"10.1371/journal.pone.0040274", "scopus"=>"2-s2.0-84864015449", "pui"=>"365274753", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"be38138d-fbd8-38fd-9392-ad0dc53cf832", "abstract"=>"Activation of nuclear factor κB (NF-κB) by interleukin-1β (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-κB dependent resynthesis of its own inhibitor IκBα. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-κB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of IκBα recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKKβ phosphorylation is shown to be a decisive process in IκBα degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. In silico knockout experiments show that translational inhibition is predominantly responsible for lack of IκBα recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of IκBα. This shows that the processes leading to activation of transcription factor NF-κB upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting.", "link"=>"http://www.mendeley.com/research/analysing-role-uvbinduced-translational-inhibition-pp2ac-deactivation-nf%CE%BAb-signalling-using-minimal", "reader_count"=>14, "reader_count_by_academic_status"=>{"Researcher"=>5, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Professor"=>2}, "reader_count_by_user_role"=>{"Researcher"=>5, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>9}, "reader_count_by_subdiscipline"=>{"Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Germany"=>1, "India"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/607234"], "description"=>"<p>(<b>A</b>) The models M<sub>Ref</sub> and M<sub>T</sub> predict markedly different IκBα concentrations following IL-1 and UVB stimulation and addition of proteasome inhibitor MG132 15 min post stimulation. The proposed experiment follows the concentration course predicted by the reference model. This confirms the hypothesis that both PP2Ac deactivation and translational inhibition are relevant processes for the lack of IκBα recurrence. KB cells were left untreated or stimulated with IL-1+UVB for the indicated time points. The proteasome inhibitor MG132 (MG) was applied 1 h in advance (−1 h) or 15 min after initial IL-1 stimulation (+15′). The status of IκBα protein was determined by Western blot analysis. Equal loading was monitored by reprobing the membrane with an anti α-tubulin antibody. The quantified blots were standardised to an initial value of 1. Parameter values were optimised using the data for IL-1, IL-1+UVB and UVB, but not for IL-1+UVB+MG132 stimulation. (<b>B</b>) Experimental predictions are perfectly in line with IκBα concentrations following CHX stimulation. KB cells were left untreated or stimulated with the translation inhibitor cycloheximide (CHX) for the indicated time points. The status of IκBα protein was determined by Western blot analysis. Equal loading was monitored by reprobing the membrane with an anti α-tubulin antibody. Protein bands shown are extracted from the same membrane under identical conditions. Parameter values were optimised using the data for IL-1, IL-1+UVB, UVB and IL-1+UVB+MG132 stimulation, but not for CHX stimulation.</p>", "links"=>[], "tags"=>["genetics and genomics", "molecular biology", "cell biology", "oncology", "mathematics"], "article_id"=>277725, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040274.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_prediction_and_validation_/277725", "title"=>"Model prediction and validation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-18 02:08:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/607100"], "description"=>"<p>System variables are depicted in green, inputs are depicted in red. Abbreviations and parameter names are explained in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040274#pone.0040274.s007\" target=\"_blank\">Tables S1</a> and <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040274#pone.0040274.s008\" target=\"_blank\">S2</a>. The model variants lacking translational inhibition or PP2Ac deactivation are implemented by setting <i>uvinh</i> = 0 or <i>k<sub>uv</sub></i> = 0, respectively.</p>", "links"=>[], "tags"=>["genetics and genomics", "molecular biology", "cell biology", "oncology", "mathematics"], "article_id"=>277585, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040274.g001", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Schematic_representation_of_the_reference_model_/277585", "title"=>"Schematic representation of the reference model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-18 02:06:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/607176"], "description"=>"<p>Assuming both UVB induced PP2Ac deactivation and translational inhibition, the model convincingly reproduces the experimental data for IL-1 (10 ng/ml), IL-1 (10 ng/ml) + UVB (300 J/m<sup>2</sup>) and UVB (300 J/m<sup>2</sup>) stimulation. Experimental data and standard deviations (blue) of phosphorylated IKKβ, total cellular IκBα and nuclear NF-κB are compared to the results of the model (red) fitted to these data. The NF-κB time courses were scaled to a mean of 1 and subsequently averaged. IκBα Western blots were standardised to an initial value of 1.</p>", "links"=>[], "tags"=>["genetics and genomics", "molecular biology", "cell biology", "oncology", "mathematics"], "article_id"=>277661, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040274.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_results_in_the_reference_model_/277661", "title"=>"Model results in the reference model.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-18 02:07:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/607333"], "description"=>"<p>Model results of model M<sub>Ref</sub> for protein levels with <i>k<sub>pconst</sub></i> as determined by fitting (red), ten fold larger <i>k<sub>pconst</sub></i> (black) and ten fold lower <i>k<sub>pconst</sub></i> (blue). For any stimulation except UVB stimulation alone, the differences are marginal.</p>", "links"=>[], "tags"=>["degradation", "uvb", "stimulation", "critically", "depends", "constitutive"], "article_id"=>277816, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040274.g004", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_I_954_B_945_degradation_upon_UVB_stimulation_critically_depends_on_constitutive_IKK_946_phosphorylation_/277816", "title"=>"IκBα degradation upon UVB stimulation critically depends on constitutive IKKβ phosphorylation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-18 02:10:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/607404"], "description"=>"<p>Knocking out the processes of UVB-induced translational inhibition or PP2Ac deactivation <i>in silico</i>, their importance for IκBα and NF-κB in model M<sub>Ref</sub> is determined. (A) Upon IL-1+UVB stimulation, lack of PP2Ac deactivation leads to recurrence of IκBα and decrease of NF-κB activity, while lack of translational inhibition only leads to a minor increase of the IκBα concentration. (B) Upon UVB stimulation, lack of PP2Ac deactivation leads to a modest decrease of IκBα concentration and to a modest increase of NF-κB activity, while lack of translational inhibition leads to a slow increase of NF-κB activity.</p>", "links"=>[], "tags"=>["uvb-induced", "translational", "inhibition", "pp2ac", "deactivation"], "article_id"=>277893, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0040274.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relevance_of_UVB_induced_translational_inhibition_and_PP2Ac_deactivation_for_I_954_B_945_and_NF_954_B_upon_UVB_8722_IL_1_stimulation_/277893", "title"=>"Relevance of UVB-induced translational inhibition and PP2Ac deactivation for IκBα and NF-κB upon UVB+/−IL-1 stimulation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-07-18 02:11:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/317011", "https://ndownloader.figshare.com/files/317043", "https://ndownloader.figshare.com/files/317072", "https://ndownloader.figshare.com/files/317108", "https://ndownloader.figshare.com/files/317137", "https://ndownloader.figshare.com/files/317171", "https://ndownloader.figshare.com/files/317203", "https://ndownloader.figshare.com/files/317259", "https://ndownloader.figshare.com/files/317307"], "description"=>"<div><p>Activation of nuclear factor κB (NF-κB) by interleukin-1β (IL-1) usually results in an anti-apoptotic activity that is rapidly terminated by a negative feedback loop involving NF-κB dependent resynthesis of its own inhibitor IκBα. However, apoptosis induced by ultraviolet B radiation (UVB) is not attenuated, but significantly enhanced by co-stimulation with IL-1 in human epithelial cells. Under these conditions NF-κB remains constitutively active and turns into a pro-apoptotic factor by selectively repressing anti-apoptotic genes. Two different mechanisms have been separately proposed to explain UV-induced lack of IκBα recurrence: global translational inhibition as well as deactivation of the Ser/Thr phosphatase PP2Ac. Using mathematical modelling, we show that the systems behaviour requires a combination of both mechanisms, and we quantify their contribution in different settings. A mathematical model including both mechanisms is developed and fitted to various experimental data sets. A comparison of the model results and predictions with model variants lacking one of the mechanisms shows that both mechanisms are present in our experimental setting. The model is successfully validated by the prediction of independent data. Weak constitutive IKKβ phosphorylation is shown to be a decisive process in IκBα degradation induced by UVB stimulation alone, but irrelevant for (co-)stimulations with IL-1. <em>In silico</em> knockout experiments show that translational inhibition is predominantly responsible for lack of IκBα recurrence following IL-1+UVB stimulation. In case of UVB stimulation alone, cooperation of both processes causes the observed decrease of IκBα. This shows that the processes leading to activation of transcription factor NF-κB upon stimulation with ultraviolet B radiation with and without interleukin-1 costimulation are more complex than previously thought, involving both a cross talk of UVB induced translational inhibition and PP2Ac deactivation. The importance of each of the mechanisms depends on the specific cellular setting.</p> </div>", "links"=>[], "tags"=>["analysing", "uvb-induced", "translational", "inhibition", "pp2ac", "deactivation", "signalling", "mathematical"], "article_id"=>122578, "categories"=>["Cancer", "Mathematics", "Molecular Biology", "Cell Biology", "Genetics"], "users"=>["Johannes Witt", "Fabian Konrath", "Oliver Sawodny", "Michael Ederer", "Dagmar Kulms", "Thomas Sauter"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0040274.s001", "https://dx.doi.org/10.1371/journal.pone.0040274.s002", "https://dx.doi.org/10.1371/journal.pone.0040274.s003", "https://dx.doi.org/10.1371/journal.pone.0040274.s004", "https://dx.doi.org/10.1371/journal.pone.0040274.s005", "https://dx.doi.org/10.1371/journal.pone.0040274.s006", "https://dx.doi.org/10.1371/journal.pone.0040274.s007", "https://dx.doi.org/10.1371/journal.pone.0040274.s008", "https://dx.doi.org/10.1371/journal.pone.0040274.s009"], "stats"=>{"downloads"=>11, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Analysing_the_Role_of_UVB_Induced_Translational_Inhibition_and_PP2Ac_Deactivation_in_NF_B_Signalling_Using_a_Minimal_Mathematical_Model/122578", "title"=>"Analysing the Role of UVB-Induced Translational Inhibition and PP2Ac Deactivation in NF-κB Signalling Using a Minimal Mathematical Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-07-18 00:42:58"}

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Relative Metric

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