Mirit Aladjem

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Kurt Kohn
Mirit Aladjem
John Weinstein
http//discover.nci.nih.gov
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On the importance of clear and precise diagrams
Edward R. Tufte on visual representation of
evidence, quoted by Michael Shermer in Sci. Amer.
April 2005
Good displays of data help to reveal knowledge
relevant to understanding mechanism, process
cause and effect
Clear and precise seeing becomes as one with
clear and precise thinking.
Simple design, intense content.
Aim for minimum number of different symbols.
maximum mechanistic detail.
http//discover.nci.nih.gov
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Diagrams can be a tremendous aid in thinking
clearly about a model, in predicting possible
experimental outcomes, and in conveying the model
to others. Ideker, Galitski Hood (2001)
Annu Rev Genomics Hum Genet, 2 343-372 Without
consistent and unambiguous rules for
representation, not only is information lost, but
misinformation could be disseminated.
Kurata, Matoba Shimizu (2003) Nucleic Acids
Res, 314071-4084. The diagrams commonly used
to show bioregulatory schemes are often
incomplete and ambiguous. Pirson et al.
(2000) Trends Cell Biol, 10 404-408
http//discover.nci.nih.gov
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ErbB-induced signaling pathways.
MARMOR, SKARIA, YARDEN (2004) Int. J. Radiation
Oncology Biol. Phys. 58 903913
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Molecular Interaction Map (MIM) notation
Kohn et al. Molec. Biology Cell 17 1-13 (2006).
http//discover.nci.nih.gov
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x
x A B
Kohn et al. Molec. Biology Cell 17 1-13 (2006).
http//discover.nci.nih.gov
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x
x phosphorylated A
P
Kohn et al. Molec. Biology Cell 17 1-13 (2006).
http//discover.nci.nih.gov
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Three types of MIMs

• Heuristic
• Explicit
• Combinatorial

http//discover.nci.nih.gov
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Heuristic MIMs are canonical
Cell type independent
Process independent
Cell compartment independent

• They show the interactions that can occur when
  molecules are in the same place at the same time.

Heuristic helping to discover or learn
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Chk2 MIM (Molecular Interaction Map)
http//discover.nci.nih.gov/mim
Click Chk2
eMIM electronic Interactive MIM
Pommier 2006 Clin. Cancer Res.
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ATM activates p53 by at least 4 coherent pathways
Kohn, Aladjem, Kim, Weinstein Pommier
Molecular Systems Biology 10.1038 (2006)
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Explicit MIMs are unambiguous

• They can be used for computer simulation.

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Properties of switch-like bioregulatory networks
studied by simulation of the hypoxia response
control system
Kurt W. Kohn, Joseph Risst, Olga Aprelikova t,
John N. Weinstein, Yves Pommier, and J. Carl
Barrett t
Laboratory of Molecular Pharmacology and
tLaboratory of Biosystems, Center for Cancer
Research, National Cancer Institute, Bethesda,
Maryland
Corresponding author 301-496-2769. Email
kohnk_at_dc37a.nci.nih.gov
Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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Switch-like HRE response to low oxygen levels
Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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As ARNT varies, transition occurs within a
similar oxygen level. HRE occupancy is
independent of ARNT levels at high oxygen levels
Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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As VHL varies, transition occurs within a similar
oxygen level. HRE occupancy is independent of VHL
at low oxygen levels
Mol. Biol. Cell, (2004) 15 3042
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Oxygen transition varies as proline hydroxylase
(PH3,3) varies
Mol. Biol. Cell, (2004) 15 3042
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Mol. Biol. Cell, (2004) 15 3042
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mRNA kinetics in response to various oxygen levels
Mol. Biol. Cell, (2004) 15 3042
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Kohn et al (2006) Molec. Systems Biol. 10.1038
Combinatorial MIMs

• combinatorial interpretation assumes that all
  interactions can occur simultaneously in any
  combination (transitive property), while
  heuristic interpretation is non-committal in this
  regard.
• In both interpretations, contingency symbols can
  be used to assert particular dependencies.
• Both can be used for simulation.

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Signaling from receptor tyrosine kinases via
Ras MIM corresponding to Lodish et al. figs.
20-22,23,28 and Kolch et al. 2000 Biochem. J.
351289
Heuristic helping to discover or learn
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ErbB-inhibitors used for cancer treatment.
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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Kohn et al (2006) Molec. Systems Biol. 10.1038
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An explicit model of signaling from EGFR
Kohn et al. Molecular Systems Biology 10.1038
(2006)
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Connection table differential equations
Kohn, Aladjem, Kim, Weinstein Pommier Molec.
Systems Biol. 10.1038 (2006)
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Combinatorial model of Blinov et al. 2006,
BioSystems 83136-51
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Reaction classes defined in the combinatorial
model of Blinov et al BioSystems 83 136-151
(2006)
Kohn, Aladjem, Kim, Weinstein Pommier
Molecular Systems Biology 10.1038 (2006)
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Summary -- Conclusions

• Molecular Interaction Maps (MIM) can be applied
  to various biological systems (http//discover.nci
  .nih.gov/mim/)
• p53, cell cycle, DNA repair (Kohn, KW. Mol.
  Biol. Cell, 1999, 10 2703)
• Cell cycle (Médecine Sciences Nature
  Encyclopedia of the Human Genome)
• Replication initiation (Science STKE, 2004, pe.
  8)
• Chk2/ATM pathway (Current Topics Med. Chem. 2003,
  3 271)
• Apoptosis Bcl-2, NFkB, Akt/PKB (Oncogene 2004,
  23 2934)
• Apoptosis c-Abl (Current Med Chem Anticancer
  Agents, 2003, 3 271)
• EGFR (Mol Syst Biol. 2006, 10 1038)
• Myc (http//discover.nci.nih.gov/mim/)
• MIMs allow compact and thorough compilation
  organization of scientific knowledge.
• MIMs can be applied to pharmacological targets to
  better understand and predict biological
  responses in normal and pathological tissues.
• MIM can be used as a first step for modeling and
  quantitative computer simulation of molecular
  pathways.

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Kurt W. Kohn Mirit I. Aladjem John N.
Weinstein Yves Pommier Molec. Biology Cell
17 1-13 (2006). MIM notation definitions and
rules. Can be used as reference or
tutorial. Kurt W. Kohn Mirit I. Aladjem John
N. Weinstein Yves Pommier Molecular Systems
Biology 10.1038 (2006). MIM compared to other
notations. MIM can depict combinatorial
complexity. MIM can depict both explicit and
combinatorial models for simulation. http//disco
ver.nci.nih.gov/mim/ Electronic MIMs
(eMIMs). Links to other databases. Kurt W. Kohn
Joseph Riss Olga Aprelikova Yves Pommier J.
Carl Barrett Molec. Biology Cell 15 3042-3052
(2004). MIM and simulation of network models. A
switch-like model of the response to
hypoxia. kohnk_at_mail.nih.gov
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NCI Kurt Kohn Mirit Aladjem Sohyoung
Kim John Weinstein Margo Sunshine Hong Cao
David Kane Joseph Riss Yves Pommier
Silvio Parodi Stefania Pasa Geoffrey
McFadden Michael Blinov