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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.

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Smoothened (Smo) in Basal Cell Carcinoma

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  1. Smoothened (Smo)in Basal Cell Carcinoma Thomas Edwards BIOL 445 26 March 2009

  2. Hedgehog Signaling Pathway Review • Active during embryonic development. • Highly conserved • Integral to the formation of important body systems in vertebrates. • Also active after development.

  3. Hedgehog Signaling Pathway Review

  4. Protein Structure and Mechanism of Smoothened in the Hedgehog Pathway • Seven Transmembrane Domain Protein • Patched removes sterols, inhibiting Smo activity.

  5. Smoothened Gene Information • Encoded by a 35 kilobase (kb) gene. • Made up of 12 exons. • Found at 7q31-31. • Proto-oncogenic

  6. 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.

  7. 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.

  8. Transfection and Transgenic Mice • Transfecting mice fibroblasts caused phenotypic transformation. • Overexpression of Smoothened in mice causes skin lesions similar to BCC to spontaneously form.

  9. 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.

  10. References Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. 2006. Hedgehog signalling in skin development and cancer. Exp Dermatol 15(9):667-77. Corcoran RB and Scott MP. 2006. Oxysterols stimulate sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc Natl Acad Sci U S A 103(22):8408-13. Daya-Grosjean L and Sarasin A. 2005. The role of UV induced lesions in skin carcinogenesis: An overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 571(1-2):43-56. 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. Incardona JP, Gruenberg J, Roelink H. 2002. Sonic hedgehog induces the segregation of patched and smoothened in endosomes. Current Biology 12(12):983-95. Østerlund T and Kogerman P. 2006. Hedgehog signalling: How to get from smo to ci and gli. 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. Mol Biol Cell; Mol Biol Cell 19(12):5478-89. Ruiz-Gómez A, Molnar C, Holguín H, Mayor J, Federico, de Celis JF. 2007. The cell biology of smo signalling and its relationships with GPCRs. Biochimica Et Biophysica Acta (BBA) - Biomembranes 1768(4):901-12. Weinberg RA. 2007. The biology of cancer. New York, NY: Garland Science. Xie J, Murone M, Luoh S, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam C, Hynes M, Goddard A, et al. 1998. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature 391(6662):90-2.

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