Unknown

Dataset Information

0

A systems biology dynamical model of mammalian G1 cell 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.

SUBMITTER: Haberichter T 

PROVIDER: S-EPMC1828753 | BioStudies | 2007-01-01

REPOSITORIES: biostudies

Similar Datasets

2007-01-01 | S-EPMC2092387 | BioStudies
2009-01-01 | S-EPMC2657433 | BioStudies
2013-01-01 | S-EPMC3667761 | BioStudies
2018-01-01 | S-EPMC5834273 | BioStudies
1000-01-01 | S-EPMC5543859 | BioStudies
2020-01-01 | S-EPMC7213986 | BioStudies
2014-01-01 | S-EPMC3897739 | BioStudies
2003-01-01 | S-EPMC1223278 | BioStudies
2012-01-01 | S-EPMC3361763 | BioStudies
2020-01-01 | S-EPMC7576148 | BioStudies