RT Journal Article
SR Electronic
T1 An Effective Model of HL-60 Differentiation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 029066
DO 10.1101/029066
A1 Ryan Tasseff
A1 Holly A. Jensen
A1 Johanna Congleton
A1 Andrew Yen
A1 Jeffrey D. Varner
YR 2015
UL http://biorxiv.org/content/early/2015/10/14/029066.abstract
AB We present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes a key architectural feature of ATRA-induced differentiation, positive feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. The model, which was developed by integrating logical rules with kinetic modeling, was significantly smaller than previous models. However, despite its simplicity, it captured key features of ATRA induced differentiation of HL-60 cells. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. These findings, combined with other literature evidence, suggest that positive feedback is central to a diversity of cell fate programs.Index Terms—Mathematical modeling, systems biology