Modeling reveals that dynamic regulation of c-FLIP levels determines cell-to-cell distribution of CD95-mediated apoptosis

Hannu Toivonen, Annika Meinander, Tomoko Asaoka, M Westerlund, Frank Pettersson, A Mikhailov, John Eriksson, Henrik Saxén

    Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

    11 Citeringar (Scopus)

    Sammanfattning

    The expression levels of caspase-8 inhibitory c-FLIP proteins play an important role in regulating death receptor-mediated apoptosis, as their concentration at the moment when the death-inducing signaling complex (DISC) is formed determines the outcome of the DISC signal. Experimental studies have shown that c-FLIP proteins are subject to dynamic turnover and that their stability and expression levels can be rapidly altered. Even though the influence of c-FLIP on the apoptotic behavior of a single cell has been captured in mathematical simulation studies, the effect of c-FLIP turnover and stability has not been investigated. In this study, a mathematical model of apoptosis was developed to analyze how the dynamic turnover and stability of the c-FLIP isoforms regulate apoptotic signaling for both individual cells and cell populations. Intercellular parameter and concentration distributions were used to describe the behavior of cell populations. Monte-Carlo simulations of cell populations showed that c-FLIP turnover is a key determinant of death receptor responses. The fact that the developed model simulates the state of whole cell populations makes it possible to validate it by comparison with empirical data. The proposed modeling approach can be used to further determine limiting factors in the DISC signaling process.
    OriginalspråkOdefinierat/okänt
    Sidor (från-till)18375–18382
    TidskriftJournal of Biological Chemistry
    Volym286
    Utgåva21
    DOI
    StatusPublicerad - 2011
    MoE-publikationstypA1 Tidskriftsartikel-refererad

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