title: SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of suppressor-of-fused in pancreatic cancer cell.
abstract: As a physically binding protein of GLI1 transcription factor, Suppressor-of-Fused (SUFU) has been placed in the center of negative regulation of Hedgehog (Hh) signaling. SUFU tethers GLI1 in cytoplasm, and in some circumstances, it moves into the nucleus in association with GLI1, leading to the suppression of GLI1 target gene expression by recruiting a corepressor complex. The activated transcriptional function of GLI1 is important for cellular proliferation in a variety of human cancers. However, it has not been revealed how GLI1 is derepressed from SUFU-mediated suppression. Here, we show SCL/TAL1 interrupting locus (SIL) product, a cytoplasmic protein overexpressed in pancreatic ductal adenocarcinoma (PDA), is responsible for the derepression of GLI1. We found SIL associated with the carboxyl terminus of SUFU, one of two distinct GLI1-binding domains, and this association was responsible for cytoplasmic tethering of SUFU. Overexpressed SIL attenuated SUFU-mediated cytoplasmic tethering and target gene suppression of GLI1. Knockdown of SIL in PDA cells conversely induced the nuclear accumulation of SUFU in association with GLI1 and the transcriptional suppression of GLI1 target genes. Importantly, we also showed that oncogenic K-RAS, and not Sonic hedgehog, enhanced the SIL association with the amino-terminus of SUFU, the other GLI1-binding domain that led to further increase of nuclear translocation of GLI1. These results uncover the role of SIL in derepressing GLI1 from the negative control of SUFU, which is a crucial step for activating Hh signaling in cancer cells.
authors.affiliation: Department of Pathology and Promoting Center for Clinical Research, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan. kkasai@amugw.aichi-med-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Kasai
authors.forename: Shingo
authors.initials: S
authors.lastname: Inaguma
authors.forename: Akiko
authors.initials: A
authors.lastname: Yoneyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras); D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D000071676:Zinc Finger Protein GLI1; D018631:ras Proteins / Q000502:physiology
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C509239:SHH protein, human; C071236:STIL protein, human; C490764:SUFU protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins