Colon cancer is the second

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Colon cancer is the second leading cause of
cancer deaths in the U.S.
Polyps, the first stage In tumor development
http//www.clevelandclinic.org/registries/inherite
d/fap.htm
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One gene mutated in the progression to
malignancy is K-ras
Lodish et al. Fig. 24-6
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Oncogenes relieve contact inhibition. This can
be visualized in culture by focus formation
Transfect with H-ras
Transfect with H-ras (close-up)
J Biol Chem 2002 27710813-23 Fiordalisi et al.
J Virol 2000 741008-13 Yoshioka et al.
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Isolation of the first oncogene
Lodish et al. Fig. 24-4
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Lipid modification of ras helps target it to the
plasma membrane
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Farnesyltransferase inhibitors offer a way of
reducing ras activity
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Farnesyltransferase inhibitors offer a way of
reducing ras activity
R115777 or lonafarnib
Phase II trials Leukemias (esp. AML/CML)
Initial results promising (also Advanced
Multiple Myeloma) Urothelial tract (with
gemcitabine) in progress Pancreatic cancer
(with gemcitabine) no improvement Colorectal
cancer (with Irinotecan) just beginning Small
cell lung cancer (with Taxol) Discontinued.
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Ras encodes a GTPase that is active when bound
to GTP
Lodish et al. Fig. 20-5
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Oncogenic Ras is stuck in the GTP-bound state
Ras G12V
Lodish et al. Fig. 20-5
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The activity of Ras is regulated by GEFs and GAPs
Lodish et al. Fig. 20-22
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Ligand binding activates RTKs by dimerization
Lodish et al. Fig. 20-21
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The RTK-ras pathway Part 1
Lodish et al. Fig. 20-23
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SH2 domains allow effector proteins to bind
activated receptors
Alberts et al. Fig. 15-49
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The RTK-ras pathway Part 2
Lodish et al. Fig. 20-23
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Ras activation triggers a kinase cascade
Lodish et al. Fig. 20-28
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RTK signaling ultimately leads to activation of a
transcription factor
Gilbert Fig. 6.14
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The eye of a fly Key to learning how Ras and
RTKs work
Lodish et al. Fig. 20-24
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Did you say flies?
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Did you say flies?
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This is all I need to know
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But wait--flies provided the Key to learning
how Ras and RTKs work
Lodish et al. Fig. 20-24
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Each ommatidium is built by a series of
cell-cell interactions
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Sevenless is required to specify the R7
photoreceptor
Wild-type
sevenless mutant
Lodish et al. Fig. 20-24
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Sevenless encodes an RTK
Lodish et al. Fig. 20-25
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Looking for other players in the pathway using
genetics
R7 present
sev pathway activity
sev threshhold

R7 absent
wild type sev- sevts sevts
sevts enh/
22.7o C 24.3o C 22.7o C
Lecture slides of Gian Garriga, UC Berkeley
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A number of genes were found that might function
in the RTK pathway
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A number of genes were found that might function
in the RTK pathway
Sos
Ras
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Ras acts downstream of the RTK Sevenless
Lodish et al. Fig. 20-25
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The signal transduction pathway should look
familiar
Alberts et al. Fig. 15-53
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Flies were bad enough, but worms!?
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Hermaphrodites do it by themselves
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Cell ablations demonstrate that a signal From
the anchor cell induces the vulva
Alberts et al. Fig. 21-41
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How can we figure out how to build a vulva?
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How can we figure out how to build a
vulva? GENETICS!
Vul bag of worms
Normal vulva
Muv
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The first two vul mutations identify the anchor
cell signal and its receptor
Alberts et al. Fig. 21-44
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How can we figure out more about how to build a
vulva? MORE GENETICS!
Vul bag of worms
Normal vulva
Muv
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The vul mutations define the RTK-Ras pathway
Alberts et al. Fig. 21-44
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Parallels in the RTK/ras pathways of humans,
flies and worms
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The RTK-Ras pathway offers drug targets for
cancer treatment
e.g., the Raf kinase inhibitor sorafenib (also
inhibits the RTKs VEGFR, PDGFR, and Kit)
Approved for treatment of advanced renal cell
carcinoma (Jan. 2006) Increased survival in
Phase III liver cancer trial and approved for
inoperable form (Nov. 2007)
In clinical trials for melanoma and lung cancer
Alberts et al. Fig. 21-44