Regulation of the G1-S Transition of the Mammalian Cell Cycle
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This CellML model has been recoded to remove the reaction element. The model opens in PCEnv and COR but unfortunately it does not run due to there being 'circular arguments' (COR) or the model being 'under-constrained' (PCEnv). At the moment this is a limitation of the simulation software because it is unable to process nonlinear
algebraic equations that must be solved iteratively at each time step.
Model Structure
In order to better understand developmental and tumour biology, extensive research on the control of the mammalian cell cycle is being carried out. At the protein level, several molecules play a role in the control of the G1-S transition of the cell cycle. Specifically, G1 cyclins such as cyclin E are known to form phosphorylated complexes with cyclin dependent kinases (cdk's, such as cdk2). These complexes, which can be inhibited by other proteins, can phosphorylate pocket proteins such as pRb. Hyperphosphorylation of pRb occurs at the time of E2F-1 release. This transcription factor initiates the transcription of genes involved in S phase activities, including DNA polymerase.
Hatzimanikatis, Lee and Bailey capture the components and interactions of cyclin E, cdk2, pRb, inhibitor and E2F-1 during the G1-S transition of the cell cycle in their mathematical model (see the figure below).
The complete original paper reference is cited below:
A Mathematical Description of Regulation of the G1-S Transition of the Mammalian Cell Cycle, V. Hatzimanikatis, K. H. Lee and J. E. Bailey, 1999,
Biotechnology and Bioengineering
, 65, 631-637. (A PDF version of the article is available for Journal Members on the Biotechnology and Bioengineering website.) PubMed ID: 10550769
diagram of the cell cycle
A schematic diagram of the reactions involved during the G1-S transition of the mammalian cell cycle.
C
cyclin E
$\frac{d C}{d \mathrm{time}}=\mathrm{Vs}+\mathrm{gamma}\mathrm{V2}-\mathrm{gamma}\mathrm{V1}+\mathrm{Vd}$
K
cdk2
$\frac{d K}{d \mathrm{time}}=\mathrm{V2}-\mathrm{V1}$
RP
hyperphosphorylated pRb
$\frac{d \mathrm{RP}}{d \mathrm{time}}=\mathrm{V3}-\mathrm{V4}$
E
E2F
$E=1.0-\mathrm{sigma}\mathrm{RE}$
KP
phosphorylated cyclin E-cdk2 complex
$\mathrm{KP}=1.0-\mathrm{KPI}+K$
KPI
phosphorylated cyclin E-cdk2 complex bound to inhibitor
$\mathrm{KPI}=\mathrm{thetaI}\mathrm{KP}I$
I
cyclin E-cdk2 complex inhibitor
$I=1.0-\mathrm{lambda}\mathrm{KPI}$
RE
hyperphosphorylated pRb bound to E2F
$\mathrm{RE}=\mathrm{thetaE}RE$
R
hypophosphorylated pRb
$R=1.0-\mathrm{RP}+\mathrm{RE}$
$\mathrm{Vs}=\mathrm{VCs}+\mathrm{Vsm}\frac{E}{\mathrm{KsE}+E}$
$\mathrm{V1}=\mathrm{V1m}\frac{C}{\mathrm{K1C}+C}\frac{K}{\mathrm{K1}+K}$
$\mathrm{V2}=\mathrm{V2m}\frac{\mathrm{KP}}{\mathrm{K2}+\mathrm{KP}}$
$\mathrm{V3}=\mathrm{V3m}\mathrm{KP}\frac{\mathrm{RE}}{\mathrm{K3}+\mathrm{RE}}$
$\mathrm{V4}=\mathrm{V4m}\frac{\mathrm{RP}}{\mathrm{K4}+\mathrm{RP}}$
$\mathrm{Vd}=C+\mathrm{VdEm}E\frac{C}{\mathrm{KdC}+C}$
The University of Auckland, Bioengineering Institute
Catherine
Lloyd
May
keyword
mammalian
cell cycle
g1-s transition
A mathematical description of regulation of the G1-S transition of the mammalian cell cycle
65
631
637
Catherine Lloyd
c.lloyd@auckland.ac.nz
Autumn
Cuellar
A
2002-10-17T00:00:00+00:00
The model has been recoded to remove the reaction element.
Biotechnology and Bioengineering
Catherine
Lloyd
May
Added publication date information.
Catherine Lloyd
Hatzimanikatis, Lee and Bailey's 1999 model of the G1-S transition of
the mammalian cell cycle.
This is the CellML descripition of Hatzimanikatis, Lee and Bailey's
1999 model of the G1-S transition of the mammalian cell cycle.
V
Hatzimanikatis
2003-04-09
K
Lee
H
1999-12-20
The University of Auckland
The Bioengineering Institute
J
Bailey
E
2008-01-02T10:51:36+13:00
10550769
This CellML model has been recoded to remove the reaction element. The model opens in PCEnv and COR but unfortunately it does not run due to there being 'circular arguments' (COR) or the model being 'under-constrained' (PCEnv). At the moment this is a limitation of the simulation software because it is unable to process nonlinear
algebraic equations that must be solved iteratively at each time step.