title: Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle.
abstract: Many antimicrobial and anti-tumour drugs elicit hormetic responses characterised by low-dose stimulation and high-dose inhibition. While this can have profound consequences for human health, with low drug concentrations actually stimulating pathogen or tumour growth, the mechanistic understanding behind such responses is still lacking. We propose a novel, simple but general mechanism that could give rise to hormesis in systems where an inhibitor acts on an enzyme. At its core is one of the basic building blocks in intracellular signalling, the dual phosphorylation-dephosphorylation motif, found in diverse regulatory processes including control of cell proliferation and programmed cell death. Our analytically-derived conditions for observing hormesis provide clues as to why this mechanism has not been previously identified. Current mathematical models regularly make simplifying assumptions that lack empirical support but inadvertently preclude the observation of hormesis. In addition, due to the inherent population heterogeneities, the presence of hormesis is likely to be masked in empirical population-level studies. Therefore, examining hormetic responses at single-cell level coupled with improved mathematical models could substantially enhance detection and mechanistic understanding of hormesis.
authors.affiliation: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Rashkov
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca, Cambridge, United Kingdom.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Barrett
authors.affiliation: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Beardmore
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca, Cambridge, United Kingdom.
authors.forename: Claus
authors.initials: C
authors.lastname: Bendtsen
authors.affiliation: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors.forename: Ivana
authors.identifier: http://orcid.org/0000-0003-3450-6854
authors.initials: I
authors.lastname: Gudelj
mesh_terms: D000818:Animals; D002468:Cell Physiological Phenomena / Q000187:drug effects*; D003198:Computer Simulation; D059165:Hormesis / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D010766:Phosphorylation / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D011494:Protein Kinases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases