A systems biology dynamical model of mammalian G1 cell cycle progression.
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.
Haberichter
Thomas
T
Gene Network Sciences Inc., Cambridge, MA 02141, USA.
Mädge
Britta
B
Christopher
Renee A
RA
Yoshioka
Naohisa
N
Dhiman
Anjali
A
Miller
Robert
R
Gendelman
Rina
R
Aksenov
Sergej V
SV
Khalil
Iya G
IG
Dowdy
Steven F
SF
D000818:Animals; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D016193:G1 Phase / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008322:Mammals; D008954:Models, Biological; D049490:Systems Biology / Q000379:methods*
D019927:Cyclin E; D036341:Intercellular Signaling Peptides and Proteins; D051357:Cyclin-Dependent Kinase 2