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.
Huntzicker
Erik G
EG
Program in Epithelial Biology, Stanford University, Stanford, California 94305, USA.
Estay
Ivette S
IS
Zhen
Hanson
H
Lokteva
Ludmila A
LA
Jackson
Peter K
PK
Oro
Anthony E
AE
D000595:Amino Acid Sequence; D000818:Animals; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014981:Xenopus; D000071676:Zinc Finger Protein GLI1
D015513:Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D046988:Proteasome Endopeptidase Complex