Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway.
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.
Yue
S
S
Laboratory of Reproductive Medicine, Nanjing Medical University, Jiangsu, PR China.
Chen
Y
Y
Cheng
S Y
SY
D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C509239:SHH protein, human; C490764:SUFU protein, human; C465570:Shh protein, mouse; C490763:Sufu protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D000071676:Zinc Finger Protein GLI1; D046988:Proteasome Endopeptidase Complex