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Title: Molecular Biology of Cancer: Content, Data and Tools for Biology Curriculum Development


1
Molecular Biology of Cancer Content, Data and
Tools for Biology Curriculum Development
Jeff Milton
2
Protein Data Bank
  • Worldwide consortium EBI, RCSB PDB, PDBj
  • Protein Data Bank Japan, Osaka University
  • Research Collaboratory for Structural
    Bioinformatics, UCSD Rutgers
  • European Bioinformatics Institute, Cambridge UK
  • As of Tuesday Feb 21, 2006 there are 35,246
    Structures
  • Protein, DNA, RNA, Protein complexes
  • Methods X-ray Crystallography (29,800) , NMR
    (5254), Electron Microscopy and other methods
    (192)
  • Data In 200 / week
  • PDB ID required for structure publication
  • Structural Genomics Initiative, NIH
  • Reduce the cost and increase the rate of
    structure determination
  • Discover protein function
  • Research biomedical problems and better
    therapeutics

3
Education at the Protein Data Bank, SDSC
  • Molecular Biology of Cancer
  • Compelling Animations by Drew Berry
  • Interviews with field experts, Vega Sciences
    Productions
  • Dissemination www.pdb.org. 100,000 unique hits
    a month from 150 different countries around the
    world
  • Software for technology enhanced learning
  • Molecular viewers, sequence viewers integrated
    with data
  • Molecule of the Month
  • Web content that highlights functional traits of
    important molecules. Written by David Goodsell,
    TSRI
  • CalIT2 Virtual Reality CAVE
  • Virtual Cave environment for enhanced
    visualization of protein structures. Directed by
    Jurgen Shulze, CalIT2

4
Molecular Biology of Cancer
Hanahan D, Weinberg RA.Department of
Biochemistry, Hormone Research Institute,
University of California at San Francisco, 94143,
USA.
5
The Hallmarks of Cancer
  1. Evading apoptosis
  2. Self-sufficiency in growth signals
  3. Insensitivity to anti-growth signals
  4. Tissue invasion metastasis
  5. Limitless replication potential
  6. Sustained angiogenesis

Hanahan D, Weinberg RA.Department of
Biochemistry, Hormone Research Institute,
University of California at San Francisco, 94143,
USA.
6
Example Cell proliferation and self-sustained
growth
  • How do cells grow and divide?
  • How do cells learn self-sustained growth?
  • What causes a cell to divide?
  • Start with synthesis of the EGF Receptor protein
  • Central Dogma
  • Localization to the cell membrane
  • Trans-membrane protein
  • EGF and EGF receptor binding ? signal into the
    cell
  • EGF-EGFR crystal structure
  • Cascade leads to a protein called RAS
  • Molecular Switch
  • ON ? cell proliferation
  • What is different about cancer cells?
  • e.g. cancer cells require little growth factors

7
  • A simple view of the pathway
  1. EGF binds to EGFR
  2. 2 EGFRs activate a series of proteins that lead
    to activation of RAS
  3. RAS is activated to the on position
  4. Cell Division
  5. RAS is turned off

Cell enters irreversibly into S phase
8
Mutations lead to self sufficient growth signals
  • Mutations in gene regulation
  • Over-expression of EGF receptor molecules
  • Cell creates growth factors that it can also bind
    to.
  • Too many receptors cause hypersensitivity to
    ambient signals
  • Mutations in protein structure
  • EGF receptor may be deployed to the membrane with
    a mutation that causes it to be stuck in the
    active state.
  • RAS or RasGAP may be mutated, preventing RAS from
    shutting off

9
  • Rational Drug Design Iressa
  • Lung Cancer
  • Small molecule that inhibits the
    auto-stimulatory action of a mutated form of the
    EGF receptor.
  • Doesnt work on over-expression of the wild
    type EGF receptor

10
Real Structural Data Integration
3D structure from the PDB highlights the
activation mechanism down to the atomic
detail. E.G. How Ras is turned off. This
structure shows the molecular switch GTP ? GDP
What are the consequences of mutations that lead
to weak interactions between these protein
structures?
PDBID 1WQ1, Scheffzek, K., Ahmadian, M.R.,
Kabsch, W., Wiesmuller, L., Lautwein, A.,
Schmitz, F., Wittinghofer, A. The Ras-RasGAP
complex structural basis for GTPase activation
and its loss in oncogenic Ras mutants. Science
v277 pp.333-338 , 1997
11
Connections to related diseases
  • Neurofibromatoses autosomal dominant
  • Neurofibroma is an enzyme that performs the same
    function as Ras-GAP. i.e. it turns RAS off in
    certain types of neurons.
  • A known germline mutation in NF1 gene causes
    failure of this mechanism and an accumulation of
    RAS in the on position. This leads to benign
    tumors in dermal, brain and spine. This usually
    leads to series developmental problems,
    blindness.
  • This debilitating disease affects 1 in
  • 3,000 males and females of
  • all races and ethnic groups.

1NF1, Scheffzek, K.,  Ahmadian,
M.R.,   Wiesmuller, L.,  Kabsch, W.,  Stege,
P.,   Schmitz, F.,  Wittinghofer, A.
Structural analysis of the GAP-related domain
from neurofibromin and its implications. EMBO
J. v17 pp.4313-4327 , 1998
12
Example Tools for curriculum development
ImageMap Query Interface. An ImageMap generator
that links schematics to a query at PDB,
GenBank, etc. Example 22 TGF-alpha growth
factors and 18 Ras signaling proteins
Sequence Viewer and Molecular Viewer for
highlighting point mutations
Virtual Lab from the ChemCollective
for Biochemistry activities Develop experiments
to determine the binding constant of RasGAP
13
  • http//www.pdb.org

14
  • Integrated software tools for enhanced
    visualization and data mining.

Enhanced searching capabilities This will be
expanded to include searching on structures
used in animations.
Integrated visualization tools
15
What is the Framework for curriculum development
and dissemination
  • Documentary design Interleave fundamental
    biological mechanisms with popular science
    concepts
  • Integrate visual animations and imagery of
    important biological processes
  • Integrate real experimental data with the biology
    and highlight directions in discovery and
    therapeutics.
  • Build tools to help curriculum developers
    integrate PDB Data with content and publish to
    the PDB web site according to relevant standards.

16
NSF, Informal Science Education (ISE)
  • Designed to increase interest, engagement and
    understanding of science, technology,
    engineering, and mathematics.
  • Not curriculum development
  • Framework for curriculum development
  • Capture important biological processes and
    provide tools for activity development
  • Teachers dont have time
  • Activities archived and disseminated according to
    national science standards.
  • Assessment?
  • http//nsf.gov/pubs/2006/nsf06520/nsf06520.htm
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