Abstract
Hedgehog signalling is crucial for development and is deregulated in several tumours, including medulloblastoma. Regulation of the transcriptional activity of Gli (glioma-associated oncogene) proteins, effectors of the Hedgehog pathway, is poorly understood. We show here that Gli1 and Gli2 are acetylated proteins and that their HDAC-mediated deacetylation promotes transcriptional activation and sustains a positive autoregulatory loop through Hedgehog-induced upregulation of HDAC1. This mechanism is turned off by HDAC1 degradation through an E3 ubiquitin ligase complex formed by Cullin3 and REN, a Gli antagonist lost in human medulloblastoma. Whereas high HDAC1 and low REN expression in neural progenitors and medulloblastomas correlates with active Hedgehog signalling, loss of HDAC activity suppresses Hedgehog-dependent growth of neural progenitors and tumour cells. Consistent with this, abrogation of Gli1 acetylation enhances cellular proliferation and transformation. These data identify an integrated HDAC- and ubiquitin-mediated circuitry, where acetylation of Gli proteins functions as an unexpected key transcriptional checkpoint of Hedgehog signalling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation
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Animals
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Cell Cycle Proteins
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Cell Line
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Cell Line, Tumor
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Cells, Cultured
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Chromatin Immunoprecipitation
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Cullin Proteins / genetics
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Cullin Proteins / metabolism*
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Electrophoresis, Polyacrylamide Gel
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Histone Deacetylase 1 / genetics
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Histone Deacetylase 1 / metabolism
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Histone Deacetylase 2 / genetics
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Histone Deacetylase 2 / metabolism
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Immunoblotting
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Immunohistochemistry
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Medulloblastoma / genetics
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Medulloblastoma / metabolism
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Mice
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NIH 3T3 Cells
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Protein Binding
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Spectrometry, Mass, Electrospray Ionization
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transferases
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
Substances
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Cell Cycle Proteins
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Cullin Proteins
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Gli1 protein, mouse
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Gli2 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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Nerve Tissue Proteins
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Oncogene Proteins
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Trans-Activators
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Zinc Finger Protein GLI1
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Zinc Finger Protein Gli2
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Kctd11 protein, mouse
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Transferases
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Histone Deacetylase 1
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Histone Deacetylase 2
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Histone Deacetylases