mgr Marta Bogdał |
Ostatnie publikacje
1. | Hat B., Kochańczyk M., Bogdał M.N., Lipniacki T., Feedbacks, bifurcations, and cell fate decision-making in the p53 system, PLOS COMPUTATIONAL BIOLOGY, ISSN: 1553-7358, DOI: 10.1371/journal.pcbi.1004787, Vol.12, No.2, pp.e1004787-1-28, 2016 Streszczenie: The p53 transcription factor is a regulator of key cellular processes including DNA repair, cell cycle arrest, and apoptosis. In this theoretical study, we investigate how the complex circuitry of the p53 network allows for stochastic yet unambiguous cell fate decision-making. The proposed Markov chain model consists of the regulatory core and two subordinated bistable modules responsible for cell cycle arrest and apoptosis. The regulatory core is controlled by two negative feedback loops (regulated by Mdm2 and Wip1) responsible for oscillations, and two antagonistic positive feedback loops (regulated by phosphatases Wip1 and PTEN) responsible for bistability. By means of bifurcation analysis of the deterministic approximation we capture the recurrent solutions (i.e., steady states and limit cycles) that delineate temporal responses of the stochastic system. Direct switching from the limit-cycle oscillations to the “apoptotic” steady state is enabled by the existence of a subcritical Neimark—Sacker bifurcation in which the limit cycle loses its stability by merging with an unstable invariant torus. Our analysis provides an explanation why cancer cell lines known to have vastly diverse expression levels of Wip1 and PTEN exhibit a broad spectrum of responses to DNA damage: from a fast transition to a high level of p53 killer (a p53 phosphoform which promotes commitment to apoptosis) in cells characterized by high PTEN and low Wip1 levels to long-lasting p53 level oscillations in cells having PTEN promoter methylated (as in, e.g., MCF-7 cell line). Słowa kluczowe: Apoptosis, Cell cycle and cell division, DNA damage, DNA repair, Phosphorylation, Biochemical simulations, Cell cycle inhibitors, Transcription factors Afiliacje autorów:
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2. | Bogdał M.N., Hat B., Kochańczyk M., Lipniacki T., Levels of pro-apoptotic regulator Bad and anti-apoptotic regulator Bcl-xL determine the type of the apoptotic logic gate, BMC SYSTEMS BIOLOGY, ISSN: 1752-0509, DOI: 10.1186/1752-0509-7-67, Vol.7, pp.1-17, 2013 Streszczenie: Background Słowa kluczowe: Apoptosis, Cell survival, Signaling pathway, Bcl-2 family, Bistability, Boolean logic, Ordinary differential equations Afiliacje autorów:
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Prace konferencyjne
1. | Bogdał M.N., Hat B., Kochańczyk M., Lipniacki T., Gates to apoptosis, XVIII National Conference Applications of Mathematics in Biology and Medicine, 2012-09-23/09-27, Krynica Morska (PL), pp.1-6, 2012 Streszczenie: p53 is the key transcription factor controlling cellular responses to oncogenic stimulation and DNA da mage. Its activity is tightly controlled by numerous feedback loops. In response to DNA damage, p53 promotes expression of proteins, which suppress cell cycle and activate DNA repair. If the damage is irreparable or the repair takes too long, the programmed cell death (apoptosis) is initiated. In the current study we analyze the apoptotic module, a part of our larger p53 pathway model. In the model, the apoptosis is triggered due to the suppression of Akt activity and/or elevated level of p53 killer.p53 killer, i.e. p53 form phosphorylated at Ser-46 (in addition to Ser-15 and Ser-20), promotes synthesis of pro- apoptotic protein Bax. In healthy cells Bax is inactive due to binding to Bcl-2, another member of Bcl-2 family proteins. Suppression of Akt activity leads to the dissociation of Bax:Bcl-2 complexes and release of Bax. Therefore, two signals may lead to the accumulation of free Bax: one coming from elevated level of p53 killer, the other resulting from decreased level of active Akt. We demonstrated that, depending on parameters, the apoptosis can be controlled by the logic gate ‘AND’ as well as gate ‘OR’. In the first case both signals are required simultaneously, while in the latter case any of the two signals suffices for the initiation of apoptosis. Afiliacje autorów:
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