Smoothened (Smo) in Basal Cell Carcinoma Thomas Edwards BIOL 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 7q 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.

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