title: Development of a culture sub-population induction model: signaling pathways synergy and taxanes production by Taxus canadensis.
abstract: Cell cultures of Taxus canadensis were subjected to exogenously applied ethylene (ET) hormone and methyl jasmonate (MJ) elicitation in factorial design experiments. Levels of extracellular taxanes, including paclitaxel, were used with principal component analysis for fault detection and real-coded genetic algorithms for parameter optimization to construct a culture sub-population induction model. Culture sub-populations were identified by the model as (1) uninduced, (2) induced to unilateral function of the ET-signaling pathway, and (3) induced to cooperation between jasmonic acid (JA)- and ET-signaling pathways. Comprehensive model results suggested greater rates of cellular induction (resulting in exogenous taxane production) by ET gas as opposed to MJ elicitation. However, cellular induction of ET-signaling pathway genes increased the rate of induction of JA-signaling pathway genes by orders of magnitude. In addition, model results showed that induction of genes leading to extracellular production of the simple taxane 10-deacetylbaccatin III was regulated by the unilateral ET-signaling pathway. However, it was suggested that further processing of this simple taxane to complex taxane structures, such as paclitaxel, required further gene induction by the JA-signaling pathway. Thus, production rate constants of exogenous complex taxanes were predicted to be an order of magnitude lower than that for the simple taxane 10-deacetylbaccatin III. The fraction of the cell culture sub-population displaying unilateral ET-signaling pathway gene induction was found inversely proportional to levels of MJ elicitation. When coupled with simple non-growth product models, levels of all extracellular taxanes were effectively predicted using the culture sub-population induction model.
authors.affiliation: Department of Chemical Engineering, Texas Tech University, Lubbock, Texas 79409, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Senger
authors.forename: Muenduen
authors.initials: M
authors.lastname: Phisalaphong
authors.forename: M Nazmul
authors.initials: MN
authors.lastname: Karim
authors.forename: James C
authors.initials: JC
authors.lastname: Linden
mesh_terms: D000085:Acetates / Q000008:administration & dosage*; D018929:Cell Culture Techniques / Q000379:methods*; D002478:Cells, Cultured; D003198:Computer Simulation; D003517:Cyclopentanes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005030:Ethylenes / Q000008:administration & dosage*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008954:Models, Biological; D054883:Oxylipins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D043823:Taxoids / Q000378:metabolism*; D020946:Taxus / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000085:Acetates; D003517:Cyclopentanes; D005030:Ethylenes; D054883:Oxylipins; D043823:Taxoids; C072239:methyl jasmonate; C036216:ethylene