Cellcycle control Chapter 7 of Aguda Friedman Amanda
- Slides: 22
Cell-cycle control Chapter 7 of Aguda & Friedman Amanda Galante Cancer Dynamics RIT September 25, 2009
Cell-cycle checkpoints • Restriction point – Regulate initiation of DNA replication • G 2 -M checkpoint – Checks DNA damage • Spindle checkpoint – Checks chromosome alignment
Restriction Point • ‘Commitment point’ for DNA replication • R point – time after which cell will enter S phase, even in absence of growth factors • Many cancers involve malfunctions of this checkpoint
G 2 DNA Damage Checkpoint (G 2 DDC) • Need to understand how coupled PD (phosphorylationdephosphorylation) cycles work • Need to establish bistability
PD cycle simple example
Transcritical Bifurcation Point
Two PD cycles Note that the eigenvalues of the Jacobian are both negative, implying a stable s. s. Could be unstable if That is, we need a destabilizing feedback loop.
Coupled PD cycles Transcritical bistability condition:
Applied to G 2 DDC
Results of G 2 DDC model • Made up rate parameters (not experimentally available) • Was able to show transcritical bistability as • Note that MPF and Cdc 25 become active at same time – ‘hallmark of transcritical bifurcation in positively coupled cyclic reactions’
PD cycle conclusions • Established existence of transcritical bifurcation point for two coupled PD cycles – Allows system to ‘check whether all components are ready for the next cell cycle event’ • MPF, Cdc 25, Wee 1 coupled PD cycles can be shown to generate bistability when including other reactions • Also applicable to R point for cyclin E/CDK 2 and Cdc 25 a
Mitotic spindle checkpoint Wikipedia - Kinetochore
Model Assumptions • • • Final kinetochore attachment Cell-cycle progression triggered by a protein c* c diffuses throughout nucleus ρ = kinetochore radius (0. 01 µm) R = nucleus radius (1 µm) D = diffusivity of c (1 µm 2/s)
Model Objectives 1. After final kinetochore attachment, a protein c which was previously in an inhibited state c* , becomes sufficiently activated at time Tb < 3 minutes 2. At steady state, c is predominantly in an inhibited state (want at least 90% inhibited, or Ac<0. 1). In this way, the system resets itself.
Model framework Doncic 2005
Direct Inhibition Model Summary: Tb = 1. 5 min – good! A = 0. 4 (i. e. 40% of c molecules are inhibited) -- too high
“Self-Propagating Inhibition” Model Summary: Tb = not happening… A < 0. 1
“Emitted Inhibition” Model Summary: Tb = 2. 5 min A = 0. 05 (i. e. the system resets itself)
Varying parameters
Conclusions of Mitotic Spindle Checkpoint Model • Single unattached kinetochore activating protein is a matter of speculation • Illustrates the impact of temporal & spatial constraints • Were able to develop a model which met the objectives – ‘Emitted Inhibition Model’
References Aguda, BD & A Friedman. Models of Cellular Regulation. Oxford University Press, 2008. Aguda, BD. (1999) ‘Instabilities in phosphorylation-dephosphorylation cascades and cell cycle checkpoints, ’ Oncogene 18, 2846 -2851. Aguda, BD. (1999) ‘A quantitative analysis of the kinetics of the G 2 DNA damage checkpoint system, ’ PNAS 96, 11352 -11357. Doncic, A, Ben-Jacob, E and N Barkai. (2006) ‘Evaluating putative mechanisms of the mitotic spindle checkpoint, ’ PNAS 102, 63326337. Other picture references • Wikipedia • http: //www. mun. ca/biology/desmid/brian/BIOL 206019/CB 19. html
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