Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 2002 Feb 15;277(7):5548-55
Date
11/24/2001Pubmed ID
11719506DOI
10.1074/jbc.M105708200Scopus ID
2-s2.0-0037085379 (requires institutional sign-in at Scopus site) 282 CitationsAbstract
The zinc finger transcription factor GLI1, which mediates Sonic hedgehog signaling during development, is expressed in several human cancers, including basal cell carcinoma, medulloblastoma, and sarcomas. We identified 147 genes whose levels of expression were significantly altered in RNA obtained from cells demonstrating a transformed phenotype with stable GLI1 expression or stable Ha-ras expression. Comparison of expression profiles from GLI1- and Ha-ras-expressing cells established a set of genes unique to GLI1-induced cell transformation. Thirty genes were altered by stable GLI1 expression, and 124 genes were changed by stable Ha-ras expression. Seven genes had altered expression levels in both GLI1- and Ha-ras-expressing cells. Genes whose expression was altered by GLI1 included cell cycle genes, cell adhesion genes, signal transduction genes, and genes regulating apoptosis. GLI1 consensus DNA-binding sequences were identified in the 5' regions of cyclin D2, IGFBP-6, osteopontin, and plakoglobin, suggesting that these genes represent immediate downstream targets. Gel shift analysis confirmed the ability of the GLI1 protein to bind these sequences. Up-regulation of cyclin D2 and down-regulation of plakoglobin were demonstrated in GLI1-amplified compared with non-amplified human rhabdomyosarcoma cells. Many of the GLI1 targets with known function identified in this study increase cell proliferation, indicating that GLI1-induced cell transformation occurs through multiple downstream pathways.
Author List
Yoon JW, Kita Y, Frank DJ, Majewski RR, Konicek BA, Nobrega MA, Jacob H, Walterhouse D, Iannaccone PMESH terms used to index this publication - Major topics in bold
Amino Acid MotifsAnimals
Apoptosis
Base Sequence
Biotinylation
Blotting, Northern
Cell Adhesion
Cell Line, Transformed
Cyclin D2
Cyclins
Cytoskeletal Proteins
DNA, Complementary
Desmoplakins
Down-Regulation
Humans
In Situ Hybridization
Insulin-Like Growth Factor Binding Protein 6
Models, Biological
Molecular Sequence Data
Oligonucleotide Array Sequence Analysis
Oncogene Proteins
Osteopontin
Phenotype
Protein Binding
Protein Structure, Tertiary
RNA
RNA, Messenger
Rats
Recombinant Fusion Proteins
Rhabdomyosarcoma
Sialoglycoproteins
Signal Transduction
Trans-Activators
Transcription Factors
Tumor Cells, Cultured
Up-Regulation
Zinc Finger Protein GLI1
gamma Catenin
ras Proteins
