Smoothened Joe Vukina April 5, 2007

Outline Introduction and pathway Normal function of smoothened and knockouts Cancer: when smoothened goes wrong Treatments?

Introduction Smo is a proto- oncogene Huangfu and Anderson

Introduction Predicted structure of SMO protein Xie et al.

Background

Downstream Targets Wetmore, Cynthia, 2003.

Structure is mostly conserved Huangfu and Anderson

Knockouts Null mutations are shown to be lethal!! Zhang et al.

Mutations Two mutations shown to be most common in BCC.

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.

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.

Overexpression of Smo Overexpression of Smo in mice Xie, Murone, and Luoh et al.

Prevention Wear sunscreen!!!!

Treatment Cyclopamine Plant derived steroidal alkaloid Historically, sheep eating a plant containing the compound would have offspring with severe defects.

Treatment Cylcopamine has been shown to inhibit the hedgehog pathway by directly binding Smo

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.

Questions?