PMID- 18829525
OWN - NLM
STAT- MEDLINE
DCOM- 20081126
LR  - 20161124
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 19
DP  - 2008 Oct 1
TI  - SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of 
      suppressor-of-fused in pancreatic cancer cell.
PG  - 7723-9
LID - 10.1158/0008-5472.CAN-07-6661 [doi]
AB  - 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.
FAU - Kasai, Kenji
AU  - Kasai K
AD  - 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
FAU - Inaguma, Shingo
AU  - Inaguma S
FAU - Yoneyama, Akiko
AU  - Yoneyama A
FAU - Yoshikawa, Kazuhiro
AU  - Yoshikawa K
FAU - Ikeda, Hiroshi
AU  - Ikeda H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (GLI1 protein, human)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KRAS protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SHH protein, human)
RN  - 0 (STIL protein, human)
RN  - 0 (SUFU protein, human)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Carcinoma, Pancreatic Ductal/*genetics/pathology
MH  - Cell Nucleus/metabolism
MH  - Cells, Cultured
MH  - Down-Regulation/genetics
MH  - Gene Expression Regulation, Neoplastic
MH  - Hedgehog Proteins/physiology
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/metabolism/*physiology
MH  - Models, Biological
MH  - Pancreatic Neoplasms/*genetics/pathology
MH  - Protein Binding
MH  - Proto-Oncogene Proteins/physiology
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Repressor Proteins/metabolism/*physiology
MH  - Transcription Factors/*genetics
MH  - Transfection
MH  - Zinc Finger Protein GLI1
MH  - ras Proteins/physiology
EDAT- 2008/10/03 09:00
MHDA- 2008/12/17 09:00
CRDT- 2008/10/03 09:00
PHST- 2008/10/03 09:00 [pubmed]
PHST- 2008/12/17 09:00 [medline]
PHST- 2008/10/03 09:00 [entrez]
AID - 68/19/7723 [pii]
AID - 10.1158/0008-5472.CAN-07-6661 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Oct 1;68(19):7723-9. doi: 10.1158/0008-5472.CAN-07-6661.