Cancer 5 lectures John Edwards Jan 2003

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Scenario 2b Excessive proliferation Growth
factor signalling PDGF Receptor
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Excessive proliferation
Receptor tyrosine kinase e.g. PDGF receptor
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Oncogenes were first identified because RNA
retro-viruses picked them up by accident
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For replication, RNA reverse-transcribed to DNA
and inserted in host chromosomes. Can be chance
integration beside oncogene so on transcription
virus acquires host sequence
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5 oncogenes to learn
Gene Proto-oncogene product
ras Signal relay G-protein (rat sarcoma)
sis Growth factor (monkey sarcoma) erb
B Growth factor receptor tyrosine kinase
(chicken erythroblastoma) PDGFR Growth
factor receptor tyrosine kinase
src Non-receptor tyrosine kinase (Chicken
sarcoma)
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Only a certain subset of cell types is sensitive
to transformation by v-sis Fibroblasts, vascular
endothelial cells, smooth muscle cells, all
involved in wound repair. Why should this be?
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Protein phosphorylation is crucial in much cell
signalling
Product is a phosphate ester

• Adds negative charge where formerly none

• Potential for 3 H-bonds, salt links, in specific
  geometry

• On or off in seconds

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Serine (S) phosphate
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Threonine (T) phosphate
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Tyrosine (Y) phosphate
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Many receptors for growth factors are RPTKs
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(Extracellular domain also functions to keep
molecules apart)
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Ras (from Rat sarcoma) an important player
because

• 1/4 of all human tumours have ras mutations

• In animal models ras mutations initiate tumours

• Gene product p21ras is archetype of large
  family of small cytoplasmic G proteins involved
  in signal switching. Also related to tubulin.

• P21ras is in signalling pathway from PTKRs

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Scenario 2b Excessive proliferation Growth
factor signalling PDGF Receptor
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Excessive proliferation
Receptor tyrosine kinase e.g. PDGF receptor
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Ras mutations transform in culture Where is ras
in the GF/GFR pathway?
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Co-IP Pull Down experiment with Ab to
PDGFR Shows PDGFR interacting with various
signalling molecules, forming a cluster which has
been called signal transduction particle For
example rasGAP, PI3 kinase, Phospholipase
Cg How do these interact with PDGFR?
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Simple Modular Architecture Research Tool
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Sequence modularity of signalling proteins
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Excessive proliferation take home of 2A and
2B Cells acquire self-sufficiency for
growth-factor triggering of replication by gain
of function mutations (yielding oncogenes) in the
gf signalling pathway. In cell culture, this is
a dramatic change in phenotype morphological
transformation. Receptor tyrosine kinases are
key players
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Summary TUMOUR PROGRESSION
Excessive proliferation of cells 1,2a,2b Attract
ion of blood supply 3 Local invasion 4 Mig
ration (Blood vessels, lymphatics) 5 Re-invasion
and colonization