Back to Search
Start Over
SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of suppressor-of-fused in pancreatic cancer cell.
- Source :
-
Cancer research [Cancer Res] 2008 Oct 01; Vol. 68 (19), pp. 7723-9. - Publication Year :
- 2008
-
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.
- Subjects :
- Carcinoma, Pancreatic Ductal pathology
Cell Nucleus metabolism
Cells, Cultured
Down-Regulation genetics
Gene Expression Regulation, Neoplastic
Hedgehog Proteins physiology
Humans
Intracellular Signaling Peptides and Proteins metabolism
Models, Biological
Pancreatic Neoplasms pathology
Protein Binding
Proto-Oncogene Proteins physiology
Proto-Oncogene Proteins p21(ras)
Repressor Proteins metabolism
Transfection
Zinc Finger Protein GLI1
ras Proteins physiology
Carcinoma, Pancreatic Ductal genetics
Intracellular Signaling Peptides and Proteins physiology
Pancreatic Neoplasms genetics
Repressor Proteins physiology
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18829525
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-07-6661