Partner: Krzysztof Puszyński

Silesian University of Technology (PL)

Ostatnie publikacje
1.Hat B., Puszyński K., Lipniacki T., Exploring mechanisms of oscillations in p53 and NF-kappaB systems, IET SYSTEMS BIOLOGY, ISSN: 1751-8849, DOI: 10.1049/iet-syb.2008.0156, Vol.3, pp.342-355, 2009

Streszczenie:

A number of regulatory networks have the potential to generate sustained oscillations of irregular amplitude, but well conserved period. Single-cell experiments revealed that in p53 and nuclear factor (NF)-kB systems the oscillation period is homogenous in cell populations, insensitive to the strength of the stimulation, and is not influenced by the overexpression of p53 or NF-kB transcription factors. We propose a novel computational method of validation of molecular pathways models, based on the analysis of sensitivity of the oscillation period to the particular gene(s) copy number and the level of stimulation. Using this method, the authors demonstrate that existing p53 models, in which oscillations are borne at a saddle-node-on-invariantcircle or subcritical Hopf bifurcations (characteristic for systems with interlinked positive and negative feedbacks), are highly sensitive to gene copy number. Hence, these models cannot explain existing experiments. Analysing NF-kB system, the authors show the importance of saturation in transcription of the NF-kB inhibitor IkBa. Models without saturation predict that the oscillation period is a rapidly growing function of total NF-kB level, which is in disagreement with experiments. The study supports the hypothesis that oscillations of robust period are based on supercritical Hopf bifurcation, characteristic for dynamical systems involving negative feedback and time delay. We hypothesise that in the p53 system, the role of positive feedback is not sustaining oscillations, but terminating them in severely damaged cells in which the apoptotic programme should be initiated.

Afiliacje autorów:

Hat B.-IPPT PAN
Puszyński K.-Silesian University of Technology (PL)
Lipniacki T.-IPPT PAN
27p.
2.Puszyński K., Bertolusso R., Lipniacki T., Crosstalk between p53 and NF-kappa B systems: pro-and anti-apoptotic functions of NF-kappa B, IET SYSTEMS BIOLOGY, ISSN: 1751-8849, DOI: 10.1049/iet-syb.2008.0172, Vol.3, pp.356-367, 2009

Streszczenie:

Nuclear factors p53 and NF-kB control many physiological processes including cell cycle arrest, DNA repair, apoptosis, death, innate and adaptive immune responses, and inflammation. There are numerous pathways linking these systems and there is a bulk of evidence for cooperation as well as for antagonisms between p53 and NF-kB. In this theoretical study, the authors use earlier models of p53 and NF-kB systems and construct a crosstalk model of p53–NF-kB network in order to explore the consequences of the two-way coupling, in which NF-kB upregulates the transcription of p53, whereas in turn p53 attenuates transcription of NF-kB inhibitors IkBa and A20. We consider a number of protocols in which cells are stimulated by tumour necrosis factor-a (TNFa) (that activates NF-kB pathway) and/or gamma irradiation (that activates p53 pathway). The authors demonstrate that NF-kB may have both anti- and pro-apoptotic roles. TNFa stimulation, preceding DNA damaging irradiation, makes cells more resistant to irradiation-induced apoptosis, whereas the same TNFa stimulation, when preceded by irradiation, increases the apoptotic cell fraction. The finding suggests that diverse roles of NF-kB in apoptosis and cancer could be related to the dynamical context of activation of p53 and NF-kB pathways.

Afiliacje autorów:

Puszyński K.-Silesian University of Technology (PL)
Bertolusso R.-Rice University (US)
Lipniacki T.-IPPT PAN
27p.
3.Puszyński K., Hat B., Lipniacki T., Oscillations and bistability in the stochastic model of p53 regulation, JOURNAL OF THEORETICAL BIOLOGY, ISSN: 0022-5193, DOI: 10.1016/j.jtbi.2008.05.039, Vol.254, No.2, pp.452-465, 2008

Streszczenie:

The p53 regulatory pathway controls cell responses, which include cell cycle arrest, DNA repair, apoptosis and cellular senescence. We propose a stochastic model of p53 regulation, which is based on two feedback loops: the negative, coupling p53 with its immediate downregulator Mdm2, and the positive, which involves PTEN, PIP3 and Akt. Existence of the negative feedback assures homeostasis of healthy cells and oscillatory responses of DNA-damaged cells, which are persistent when DNA repair is inefficient and the positive feedback loop is broken. The positive feedback destroys the negative coupling between Mdm2 and p53 by sequestering most of Mdm2 in cytoplasm, so it may no longer prime the nuclear p53 for degradation. It works as a clock, giving the cell some time for DNA repair. However, when DNA repair is inefficient, the active p53 rises to a high level and triggers transcription of proapoptotic genes. As a result, small DNA damage may be repaired and the cell may return to its initial ‘‘healthy’’ state, while the extended damage results in apoptosis. The stochasticity of p53 regulation, introduced at the levels of gene expression, DNA damage and repair, leads to high heterogeneity of cell responses and causes cell population split after irradiation into subpopulations of apoptotic and surviving cells, with fraction of apoptotic cells growing with the irradiation dose.

Słowa kluczowe:

Signaling pathways, Positive and negative feedbacks, Mathematical modeling, Stochastic simulations, Apoptosis, p53, Mdm2, PTEN

Afiliacje autorów:

Puszyński K.-Silesian University of Technology (PL)
Hat B.-IPPT PAN
Lipniacki T.-IPPT PAN
4.Lipniacki T., Puszyński K., Paszek P., Brasier A.R., Kimmel M., Single TNFalpha trimers mediating NF-kappaB activation: Stochastic robustness of NF-kappaB signaling, BMC BIOINFORMATICS, ISSN: 1471-2105, DOI: 10.1186/1471-2105-8-376, Vol.8, pp.376-400, 2007

Streszczenie:

Background
The NF-κ B regulatory network controls innate immune response by transducing variety of pathogen-derived and cytokine stimuli into well defined single-cell gene regulatory events.

Results
We analyze the network by means of the model combining a deterministic description for molecular species with large cellular concentrations with two classes of stochastic switches: cell-surface receptor activation by TNFα ligand, and Iκ Bα and A20 genes activation by NF-κ B molecules. Both stochastic switches are associated with amplification pathways capable of translating single molecular events into tens of thousands of synthesized or degraded proteins. Here, we show that at a low TNFα dose only a fraction of cells are activated, but in these activated cells the amplification mechanisms assure that the amplitude of NF-κ B nuclear translocation remains above a threshold. Similarly, the lower nuclear NF-κ B concentration only reduces the probability of gene activation, but does not reduce gene expression of those responding.

Conclusion
These two effects provide a particular stochastic robustness in cell regulation, allowing cells to respond differently to the same stimuli, but causing their individual responses to be unequivocal. Both effects are likely to be crucial in the early immune response: Diversity in cell responses causes that the tissue defense is harder to overcome by relatively simple programs coded in viruses and other pathogens. The more focused single-cell responses help cells to choose their individual fates such as apoptosis or proliferation. The model supports the hypothesis that binding of single TNFα ligands is sufficient to induce massive NF-κ B translocation and activation of NF-κ B dependent genes.

Afiliacje autorów:

Lipniacki T.-IPPT PAN
Puszyński K.-Silesian University of Technology (PL)
Paszek P.-Rice University (US)
Brasier A.R.-University of Texas Medical Branch (US)
Kimmel M.-Rice University (US)