Understanding of life/death decisions at CD95
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The new article, arising from the cooperation between the group of Inna Lavrik (Division Peter H. Krammer) and Division of Roland Eils iBioS has been published in Molecular Systems Biology, the leading journal for systems biology research.
The paper features a new model, which helps to explain the dilemma that stimulation of the death receptor CD95 leads to the induction of cell death via caspases in some cells and in others leads to the activation of NF-êB, leading to increased cell proliferation. The paper demonstrates the power of systems biology analysis. The mathematical modeling together with experimental analysis of CD95 signaling showed how a subtle balance of main components of CD95 signaling determines life/death decisions. Our results support the emerging paradigm in CD95 signaling that the receptor signaling complex (death-inducing signaling complex, DISC) can act as a potent signal processor deciding between life and death. Why then would the same receptor trigger two pathways with opposing phenotypes? NF-kB is a transcription factor for the c-FLIP and the IAP family. Hence, up-regulation of these apoptosis inhibitors may maintain a threshold towards CD95-mediated apoptosis, thereby preventing unwanted apoptotic effects at low amounts of CD95L. This is especially important with respect to understanding resistance of cancer cells towards treatment involving death receptor stimulation. In these scenarios death receptor stimulation might lead not only to apoptosis but induction of additional resistance level via upregulation of apoptosis inhibitors. This work demonstrates a complexity of life/death decisions in the cell and shows that the understanding of this complexity is possible only using systems biology approaches.
Dynamics within the CD95 death-inducing signaling complex decide life and death of cells
Leo Neumann, Carina Pforr, Joel Beaudouin, Alexander Pappa, Nicolai Fricker, Peter H Krammer, Inna N Lavrik, and Roland Eils
Mol Syst Biol. 2010; 6: 352.
Published online 2010 March 9. doi: 10.1038/msb.2010.6.