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

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?