SNAIL driven by a feed forward loop motif promotes TGFβ induced epithelial to mesenchymal transition

Abstract

Epithelial to Mesenchymal Transition (EMT) plays an important role in tissue regeneration, embryonic development, and cancer metastasis. Several signaling pathways are known to regulate EMT, among which the modulation of TGFβ (Transforming Growth Factor-β) induced EMT is crucial in several cancer types. Several mathematical models were built to explore the role of core regulatory circuit of ZEB/miR-200, SNAIL/miR-34 double negative feedback loops in modulating TGFβ induced EMT. Different emergent behavior including tristability, irreversible switching, existence of hybrid EMT states were inferred though these models. Some studies have explored the role of TGFβ receptor activation, SMADs nucleocytoplasmic shuttling and complex formation. Recent experiments have revealed that MDM2 along with SMAD complex regulates SNAIL expression driven EMT. Encouraged by this, in the present study we developed a mathematical model for p53/MDM2 dependent TGFβ induced EMT regulation. Inclusion of p53 brings in an additional mechanistic perspective in exploring the EM transition. The network formulated comprises a C1FFL moderating SNAIL expression involving MDM2 and SMAD complex, which functions as a noise filter and persistent detector. The C1FFL was also observed to operate as a coincidence detector driving the SNAIL dependent downstream signaling into phenotypic switching decision. Systems modelling and analysis of the devised network, displayed interesting dynamic behavior, systems response to various inputs stimulus, providing a better understanding of p53/MDM2 dependent TGF-β induced Epithelial to Mesenchymal Transition.