Download Smoothened (Smo) in Basal Cell Carcinoma

Smoothened (Smo)
in
Basal Cell Carcinoma
Thomas Edwards
BIOL 445
26 March 2009
Hedgehog Signaling Pathway Review
• Active during embryonic development.
• Highly conserved
• Integral to the formation of important body
systems in vertebrates.
• Also active after development.
Hedgehog Signaling Pathway Review
Protein Structure and Mechanism of
Smoothened in the Hedgehog Pathway
• Seven Transmembrane Domain Protein
• Patched removes sterols, inhibiting Smo activity.
Smoothened Gene Information
• Encoded by a 35
kilobase (kb) gene.
• Made up of 12
exons.
• Found at 7q31-31.
• Proto-oncogenic
Basal Cell Carcinoma Information
• Caused by mutations
in the Hedgehog
pathway.
• A non-melanoma skin
cancer.
• 750,000 new cases
each year.
• UV exposure is the
primary risk factor.
• Considered malignant,
but rarely
metastasizes or kills.
Smoothened in Basal Cell Carcinoma
• Two possible
missense mutations.
– Arg to Gln at codon
562
– Trp to Leu at codon
535
• Somatic cell
mutations, not seen in
blood cells.
• Other mutations in the
pathway are more
common.
Transfection and Transgenic Mice
• Transfecting mice fibroblasts caused phenotypic
transformation.
• Overexpression of Smoothened in mice causes
skin lesions similar to BCC to spontaneously form.
Summary
• Smoothened encodes a transmembrane protein that is a
member of the Hedgehog Signaling Pathway.
• Smoothened protein is inhibited by Patched.
• When Hedgehog ligand is present, Patched ceases to
inhibit Smoothened which activates Gli and thus
transcription occurs.
• The Hedgehog Pathway is active predominately during
embryonic development, but also maintains adult stem cells.
• Smoothened is oncogenic. Activating mutations can be
caused by either of two missense mutations that are usually
caused by exposure to UV light.
– These mutations effect the action of Patched on Smoothened.
• Basal Cell Carcinoma is an incredibly common cancer that
can also be caused by mutations in the hedgehog ligand as
well as in Patched.
References
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pigmentosum skin tumors. Mutation Research/Fundamental and Molecular Mechanisms of
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Huangfu DD. 2006. Signaling from smo to Ci/Gli: Conservation and divergence of hedgehog
pathways from drosophila to vertebrates. Development (Cambridge) 133(1):3-14.
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Trends Cell Biol 16(4):176-80.
Philipp M, Fralish GB, Meloni AR, Chen W, MacInnes AW, Barak LS, Caron MG. 2008.
Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase.
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