Model-based investigation of the transcriptional activity of p53 and its feedback loop regulation via 14-3-3σ.
Experiments have recently shown that p53 expression can display oscillations in response to certain stress signals. In this work, mathematical modelling and bifurcation analysis are combined to investigate under which conditions the oscillation of p53 could propagate to its direct downstream transcription targets. The authors' analysis suggests that oscillations of p53 will propagate only to proteins with medium-fast mRNA and protein turnover rates. The authors retrieved data concerning the half-life of mRNA and protein for a number of p53-promoted genes and found that, according to their model, most of them are not able to inherit the oscillation of p53 because of their slow turnover rates. However, their analysis indicates that p53 oscillation may actually fine-tune the expression pattern of a protein when it is integrated with a second oscillatory signal. The authors also consider the case of additional regulatory loops affecting p53 oscillations and involving proteins transcriptionally induced by p53. Their results for 14-3-3σ, a protein that targets the p53 inhibitor MDM2 for degradation, suggest that the addition of feedback-loop regulation may modulate basic properties of p53 oscillation and induce quick cessation of them under certain physiological conditions. Moreover, the interplay between DNA damage and 14-3-3σ may induce bistability in the oscillation of p53.
Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany. jv030@informatik.uni-rostock.de
J
J
Vera
S
S
Nikolov
X
X
Lai
A
A
Singh
O
O
Wolkenhauer
D048948:14-3-3 Proteins / Q000378:metabolism*; D000465:Algorithms; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods*; D004249:DNA Damage; D005092:Exonucleases / Q000378:metabolism*; D005095:Exoribonucleases; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D008954:Models, Biological; D015233:Models, Statistical; D008962:Models, Theoretical; D009991:Oscillometry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human