Phenotype Switching during Tumor Necrosis Factor alpha signalling
Published in TNF Superfamily, 2019
Tumor Necrosis Factor alpha (TNFα) is a pleiotropic cytokine involved in phenotypic decisions such as apoptotic/necrotic death, proliferation. Aberrant TNFα signaling is implicated in numerous pathological conditions. Designing therapeutic strategies to modulate these conditions require insights into the mechanisms governing context-specific phenotypic response to TNFα. Signal transduction culminating in such responses is orchestrated by underlying molecular network of nodes interconnected by edges. Using a comprehensive, well- annotated, manually curated TNF-α signaling network, we show that a graph-theory based dimensionality reduction via modularization can lead to functionally consistent, conserved modules in the network. We identify 19 candidates which when knocked down one-at- a-time significantly disturbs the network robustness yet preserves network modularity. Boolean dynamic simulations and attractor analysis of the underlying state transition graph show that targeting cIAP1/2 and MKRN1 can lead to reliable phenotype switching from proliferation to apoptosis. Knocking off BAX-BAK and LUBAC may result in switching from apoptosis to proliferation. These combinations causing phenotype switching could be potential targets for TNFα based therapeutic strategies.
Citation
‘Hrushikesh Loya, Shubhank Sherekar, Sonal Manohar, Reshma Patil, Ganesh Viswanathan (2019). "Phenotype Switching during Tumor Necrosis Factor alpha signalling; 2019 Jun 3-7; California, USA</i>.’