Dual degradation signals control Gli protein stability and tumor formation.
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, D(N) and D(C), 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.
PubMed ID: 16421275
PMC ID: PMC1361699
Article link: Genes Dev.
Grant support: R01ARO46786 PHS HHS , R01GM60439 NIGMS NIH HHS , R01 AR054780-05 NIAMS NIH HHS , R01 AR054780 NIAMS NIH HHS
Genes referenced: gli1 shh