An Effective Model of HL-60 Differentiation

BioRxiv : the Preprint Server for Biology
Ryan TasseffJeffrey D Varner

Abstract

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 differen- tiation, 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 model- ing, 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 effec- tive 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.

Related Concepts

Cell Differentiation Process
Literature
Retinoids
Tretinoin
Guanine Nucleotide Exchange Factors
Mitogen-Activated Protein Kinase Kinases
HL-60 Cells
Research Study
Peptidylarginine deiminase type IV
Analysis

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