Theoretical and experimental evidence for hysteresis in cell proliferation.
We propose a mathematical model for the regulation of the G1-phase of the mammalian cell cycle taking into account interactions of cyclin D/cdk4, cyclin E/cdk2, Rb and E2F. Mathematical analysis of this model predicts that a change in the proliferative status in response to a change in concentrations of serum growth factors will exhibit the property of hysteresis: the concentration of growth factors required to induce proliferation is higher than the concentration required to maintain proliferation. We experimentally confirmed this prediction in mouse embryonic fibroblasts in vitro. In agreement with the mathematical model, this indicates that changes in proliferative mode caused by small changes in concentrations of growth factors are not easily reversible. Based on this study, we discuss the importance of proliferation hysteresis for cell cycle regulation.
Bai
Shaochun
S
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Goodrich
David
D
Thron
C Dennis
CD
Tecarro
Edwin
E
Obeyesekere
Mandri
M
D000465:Algorithms; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology*; D003198:Computer Simulation; D003470:Culture Media / Q000494:pharmacology; D056741:Cyclin D; D019927:Cyclin E / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005057:Eukaryotic Cells / Q000187:drug effects / Q000502:physiology*; D005347:Fibroblasts / Q000502:physiology; D016193:G1 Phase / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D003470:Culture Media; D056741:Cyclin D; D019927:Cyclin E; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases