Patched and Basal Cell Carcinoma Matt Darch

Patched

Patched Description Abbreviated Ptc Characterized as a tumor suppressor Sonic Hedgehog pathway 12 “pass” transmembrane receptor Binds to a ligand (Shh)

Sonic Hedgehog Pathway Actually named after the video game character.

Sonic Hedgehog Pathway Many functions during development Acts to set up cell fates in diverse tissues

Shh Pathway Ptc inhibits Smo Protein complex binds Gli Gli is ubiquitnated, and truncated Gli binds to DNA No transcription

Shh Pathway with Hedgehog Hedgehog binds Ptc Ptc doesn’t inhibit Smo Smo stops the complex from ubiquitnating Gli Gli binds to DNA to promote transcription

Knockouts

Ptc Knockouts Neural tube does not close. -/- Embryonic lethal in mice Shh pathway target genes turned on everywhere -/- +/-

Relevance to Cancer

Radiation Sensitivity Ptc +/- causes increased incidence of basal cell carcinoma, a form of skin cancer Tested tumorigenesis in Ptc +/- mice, by exposing to UV light Ptc +/- mice had BCC tumors in 4 months versus 11 months in Ptc +/+ mice.

Basal Cell Carcinoma Type of skin cancer Approximately 800,000 new cases in the United States this year Basal cells line the bottom most layer of epidermis Caused by chronic overexposure to the sun, sunburns

Basal Cell Carcinoma Skin Lesion Invading tumor

Treatments

Possible Treatments Prevention-WEAR SUNSCREEN! Basal Cell Carcinoma is easy to remove Removed before it can dramatically effect humans

Over inhibition of Smo: Cyclopia ligand

Treatment Continued Medulloblastoma localized to brain Frequently inoperable If inactive Ptc, then use cyclopamine to artificially regulate the pathway downstream of Ptc Currently in Clinical Trials (Genentech and Curis)

Questions?

References