MODELS OF CELLFATE REGULATION

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MBI Journal Club on
MODELS OF CELL-FATE REGULATION
Baltazar D. Aguda (bdaguda_at_gmail.com), Organizer
24 May 2006
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Lots of sources of molecular pathways!
http//www.pathguide.org
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Pathways and Networks DBs/KBs listed under
the following headings 1.
Protein-Protein Interactions (86) 2. Metabolic
Pathways (45) 3. Signaling Pathways (45) 4.
Pathway Diagrams (23) 5. Transcription
Factors/Gene Regulatory Networks (30) 6.
Protein-Compound Interactions (16) 7. Genetic
Interaction Networks (5) 8. Protein Sequence
Focus (12) 9. Other (13)
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http//www.genome.jp/kegg
Kyoto Encyclopedia of Genes Genomes (KEGG)
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http//www.biocarta.com
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PROBLEMS WITH PATHWAYS DATABASES
incompleteness, uncertainties,
inconsistencies, mostly qualitative info how to
extract dynamical models?
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CELL DEATH
Part One
necrosis
apoptosis
pictures from Alberts et al. Molecular Biology
of the Cell 4th ed.
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apoptosis
http//www-micro.msb.le.ac.uk/3035/kalmakoff/bacul
o/baculohostinteract.html
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Apoptosis in Development
pictures from Alberts et al. Molecular Biology
of the Cell 4th ed.
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CASPASES
key proteases in apoptosis
picture from Alberts et al. Molecular Biology
of the Cell 4th ed.
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Caspase Cascades
picture from Zheng Flavell, 2000
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(No Transcript)
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Bistability
s
u
Xs
s
parameter
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Basic Model
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Basic Model
v1 k1C8C3 v2 k2C3C8 v3
k3C3IAP k-3iC3IAP v4 k4C3IAP v5
k5C8 v6 k6C3 v7 k7iC3IAP v8
k8IAP k-8 v9 k9C8 k-9 v10 k10C3
k-10
Note mass-action kinetics
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Fig 2 of Eissing et al. (2004) Basic Model
0
3.2 x 103 M-1s-1
C3
k1
Steady state
Alive
Apoptotic (dead)
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Above red area no stable alive steady state
exists.
Fig 3 of Eissing et al. (2004) Basic Model
Literature data
Below blue area no second stable steady state
exists.
Below green area Solutions are complex numbers.
k1
k1 2k2
BISTABILITY REQUIRES PARAMETER VALUES BELOW RED
AND ABOVE THE BLUE GREEN AREAS.
k4
t1/2 (ln 2)/k7
k7 k8 2k5 2k6 4k9 4k10
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PROBLEMS OF THE BASIC MODEL
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Extended Model
v1 k1C8C3 v2 k2C3C8 v3
k3C3IAP k-3iC3IAP v4 k4C3IAP v5
k5C8 v6 k6C3 v7 k7iC3IAP v8
k8IAP k-8 v9 k9C8 k-9 v10 k10C3
k-10 v11 k11C8BAR k-11iC8BAR v12
k12BAR k-12 v13 k13iC8BAR
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EXTENDED MODEL
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(No Transcript)
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Reconciling single-cell and population kinetics
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picture from Zheng Flavell, 2000