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Genes & Dev. 20 (3): 276-281

Copyright © 2006 by Cold Spring Harbor Laboratory Press.

RESEARCH COMMUNICATION

Dual degradation signals control Gli protein stability and tumor formation

Erik G. Huntzicker1,3, Ivette S. Estay1,3, Hanson Zhen1, Ludmila A. Lokteva1, Peter K. Jackson2,3, and Anthony E. Oro1,3,4

1 Program in Epithelial Biology, 2 Department of Pathology, School of Medicine, and 3 Cancer Biology Graduate Program, Stanford University, Stanford, California 94305, USA

Abstract: Regulated protein destruction controls many key cellular processes with aberrant regulation increasingly found during carcinogenesis. Gli proteins mediate the transcriptional effects of the Sonic hedgehog pathway, which is implicated in up to 25% of human tumors. Here we show that Gli is rapidly destroyed by the proteasome and that mouse basal cell carcinoma induction correlates with Gli protein accumulation. We identify two independent destruction signals in Gli1, DN and DC, and show that removal of these signals stabilizes Gli1 protein and rapidly accelerates tumor formation in transgenic animals. These data argue that control of Gli protein accumulation underlies tumorigenesis and suggest a new avenue for antitumor therapy.

Key Words: Hedgehog • Gli • beta-TRCP • proteasome • basal cell carcinoma • hair follicle

Received for publication October 3, 2005. Accepted for publication December 1, 2005.

Supplemental material is available at http://www.genesdev.org.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1380906.

4 Corresponding author.

E-MAIL oro{at}cmgm.stanford.edu; FAX (650) 723-8762.

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