A systems biology dynamical model of mammalian G₁cell cycle progression

Abstract

The current dogma of G 1 cell-cycle progression relies on growth factor-induced increase of cyclin D:Cdk4/6 complex activity to partially inactivate pRb by phosphorylation and to sequester p27 Kip1 triggering activation of cyclin E:Cdk2 complexes that further inactivate pRb. pRb oscillates between an active, hypophosphorylated form associated with E2F transcription factors in early G 1 phase and an inactive, hyperphosphorylated form in late G 1 , S and G 2 /M phases. However, under constant growth factor stimulation, cells show constitutively active cyclin D:Cdk4/6 throughout the cell cycle and thereby exclude cyclin D:Cdk4/6 inactivation of pRb. To address this paradox, we developed a mathematical model of G 1 progression using physiological expression and activity profiles from synchronized cells exposed to constant growth factors and included a metabolically responsive, activating modifier of cyclin E:Cdk2. Our mathematical model accurately simulates G 1 progression, recapitulates observations from targeted gene deletion studies and serves as a foundation for development of therapeutics targeting G 1 cell-cycle progression.

RB1: a prototype tumor suppressor and an enigma

“…This selectivity suggests that the various perturbations of this "pathway" are not identical but that specific mutations have different consequences in different contexts. Data indicating that pRB retains some degree of E2F regulation in INK4A mutant cells or when phosphorylated by cyclin D-dependent kinases (Haberichter et al 2007;Narasimha et al 2014) and evidence that hyperphosphorylated pRB interacts with the mTORC2 complex and attenuates Akt activation (Zhang et al 2016) support the view that the inactivation of pRB by phosphorylation is not functionally equivalent to the mutation of the RB1 gene.…”

An Investigation of the Expression of G1-Phase Cell Cycle Proteins in Focal Cortical Dysplasia Type IIB

“…Progressive phosphorylation of Rb controls progression through the restriction point (also known as the irreversible commitment point [29]) of the G 1 phase toward S phase entry (30,31). By using 2 well-characterized antibodies specific for Rb phosphorylation sites 795 and 807/811, expression of phospho-Rb was limited to a few BCs in 5 of the FCD cases, which would overall support a lack of cyclin D/cdk4 or cyclin E/cdk2 activity.…”

Programming with models: modularity and abstraction provide powerful capabilities for systems biology

“…There are many perspectives on this problem: some properties of systems can be proved to be independent of parameter values (Feinberg 1995;Angeli et al 2004); parameters can be estimated from data in statistically meaningful ways ( Jaqaman & Danuser 2006); methods of dimensionality reduction can reduce complexity (Barbano et al 2007); some properties of systems have been found empirically to be robust to parameter variation (Alon et al 1999;von Dassow et al 2000); and both theory and empirical results suggest that, for any given phenotypic behaviour, only an exponentially small number of parameters are significant (Rand et al 2005;Gutenkunst et al 2007). We note further that both pharmaceutical and biotechnology companies are adopting modelling in drug development (Bangs & Paterson 2003;Hendriks et al 2006;Haberichter et al 2007), suggesting that model complexity is not a barrier to usefulness. Methodologies for building complex models in a flexible and controlled manner therefore become all the more important.…”