smoothened joe vukina april 5, 2007. outline introduction and pathway normal function of smoothened...
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Smoothened
Joe Vukina
April 5, 2007
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Outline
• Introduction and pathway
• Normal function of smoothened and knockouts
• Cancer: when smoothened goes wrong
• Treatments?
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Introduction
• Smo is a proto-oncogene
Huangfu and Anderson
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Introduction
• Predicted structure of SMO protein
Xie et al.
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Background
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Background
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Downstream Targets
Wetmore, Cynthia, 2003.
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Structure is mostly conserved
Huangfu and Anderson
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Knockouts
Null mutations are shown to be lethal!!
Zhang et al.
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Mutations
• Two mutations shown to be most common in BCC.
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Basal Cell Carcinoma
• Most common cancer in Caucasians.
• Increased risk for people with extensive exposure to UV light or arsenic.
• Study showed that 19 of 20 mutations showed up in sun exposed spots
Lam, Xie, and To et al.
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Basal Cell Carcinoma
• One study showed 20.6% of sporadic BCCs to contain a mutation in Smo.
• Most common treatments include surgery and chemotherapy.
Lam, Xie, and To et al.
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Overexpression of Smo
• Overexpression of Smo in mice
Xie, Murone, and Luoh et al.
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Prevention
• Wear sunscreen!!!!
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Treatment
Cyclopamine
• Plant derived steroidal alkaloid
• Historically, sheep eating a plant containing the compound would have offspring with severe defects.
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Treatment
• Cylcopamine has been shown to inhibit the hedgehog pathway by directly binding Smo
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Summary
• Smo is a proto-oncogene that when turned on promotes proliferation and gene transcription.
• Smo is part of the hedgehog pathway that is involved in neural tube, heart and gut development.
• In cancer, Smo is mutated so it cannot be inhibited by Ptc and is constitutively on.
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Questions?