Abstract
Sustained Sonic hedgehog (Shh) pathway activity is associated with tumorigenesis in a wide variety of tissues. Mutational inactivation of Shh receptor Patched (Ptch) and a downstream gene Suppressor of fused (Sufu), both of which are negative regulators of the pathway, increases susceptibility to cerebellum cancer in humans and mice. Sufu is a binding partner of Shh pathway transcription factor Gli. Recent data indicate that inactivation of Sufu, through either gene targeting in mice or RNAi-mediated silencing in cultured fibroblasts, is sufficient to turn on Shh target gene expression. Here, we report that Sufu is degraded rapidly in certain cancer cells and we show that Shh signaling promotes ubiquitination of Sufu, which leads to its destruction in the proteasomes. We identified an ubiquitin attachment site on K257 of Sufu, and showed that Sufu-K257R mutant is more potent as a transcription repressor and cell growth inhibitor because of increased stability. These results indicate that Shh signaling regulates Sufu activity by inducing its turnover via the ubiquitin-proteasome system.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Binding Sites / genetics
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Brain Neoplasms / genetics
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Brain Neoplasms / metabolism*
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Gene Silencing
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mutation, Missense
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NIH 3T3 Cells
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Patched Receptors
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Patched-1 Receptor
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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RNA, Small Interfering / genetics
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction* / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitination* / genetics
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Zinc Finger Protein GLI1
Substances
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GLI1 protein, human
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Gli1 protein, mouse
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Hedgehog Proteins
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Kruppel-Like Transcription Factors
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PTCH1 protein, human
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Patched Receptors
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Patched-1 Receptor
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Ptch1 protein, mouse
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RNA, Small Interfering
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Receptors, Cell Surface
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Repressor Proteins
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SHH protein, human
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SUFU protein, human
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Shh protein, mouse
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Sufu protein, mouse
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin
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Zinc Finger Protein GLI1
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Proteasome Endopeptidase Complex