Smoothened (Smo) in Basal Cell Carcinoma
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Smoothened (Smo)in
Basal Cell CarcinomaThomas Edwards
BIOL 44526 March 2009
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Hedgehog Signaling Pathway Review
• Active during embryonic development.
• Highly conserved
• Integral to the formation of important body
systems in vertebrates.
• Also active after development.
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Hedgehog Signaling Pathway Review
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Protein Structure and Mechanism of Smoothened in the Hedgehog Pathway
• Seven Transmembrane Domain Protein
• Patched removes sterols, inhibiting Smo activity.
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Smoothened Gene Information
• Encoded by a 35 kilobase (kb) gene.
• Made up of 12 exons.
• Found at 7q31-31.
• Proto-oncogenic
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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.
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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.
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Transfection and Transgenic Mice• Transfecting mice fibroblasts caused phenotypic
transformation.• Overexpression of Smoothened in mice causes
skin lesions similar to BCC to spontaneously form.
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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.
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