An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program.
Sci Rep
; 7(1): 14327, 2017 10 30.
Article
em En
| MEDLINE
| ID: mdl-29085021
ABSTRACT
In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing 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. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. 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. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPARg were critical to the ATRAinduced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.
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Base de dados:
MEDLINE
Assunto principal:
Tretinoína
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Células Precursoras de Granulócitos
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Redes Reguladoras de Genes
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Pontos de Checagem do Ciclo Celular
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Modelos Teóricos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article