Molecular circuits, biological switches, and nonlinear dose-response relationships.

Abstract

Signaling motifs (nuclear transcriptional receptors, kinase/phosphatase cascades, G-coupled protein receptors, etc.) have composite dose-response behaviors in relation to concentrations of protein receptors and endogenous signaling molecules. "Molecular circuits" include the biological components and their interactions that comprise the workings of these signaling motifs. Many of these molecular circuits have nonlinear dose-response behaviors for endogenous ligands and for exogenous toxicants, acting as switches with "all-or-none" responses over a narrow range of concentration. In turn, these biological switches regulate large-scale cellular processes, e.g., commitment to cell division, cell differentiation, and phenotypic alterations. Biologically based dose-response (BBDR) models accounting for these biological switches would improve risk assessment for many nonlinear processes in toxicology. These BBDR models must account for normal control of the signaling motifs and for perturbations by toxic compounds. We describe several of these biological switches, current tools available for constructing BBDR models of these processes, and the potential value of these models in risk assessment.

Discordant on/off switching of gene expression in myocytes during cardiac hypertrophy in vivo

“…There has been substantial theoretical discussion (12,32,33) and experimental modeling (34)(35)(36)(37) regarding the possibility that individual genes are regulated in an on/off or in a graded manner in individual cells. Our study provides evidence that on/off switching occurs in cardiac myocytes and confirms other observations that individual genes change expression in an on/off rather than graded manner (38)(39)(40).…”

Prenatal, Early Life, and Childhood Exposure to Genotoxicants in the Living Environment

“…Recent advances have demonstrated that molecular regulatory networks can be modelled in mathematical terms. Such approach will prevent hundreds of genotoxicological results and especially results from gene and protein arrays to serve simply as a catalogue of change (109).…”

Equilibrium switching and mathematical properties of nonlinear interaction networks with concurrent antagonism and self-stimulation

“…The self-stimulation rate in the CDM model serves as a positive-feedback memory. Self-stimulation is a common property of master switches in gene regulation and other biological signaling systems [22,17,23,24]. In fact, the CDM is a candidate model of biological switches that exhibit multi-stability (co-existence of multiple stable equilibria) [25][26][27][28][29].…”