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*
Joon Won
Yoon
§,
Yasuhiro
Kita§¶
,
Daniel J.
Frank,
Rebecca R.
Majewski¶,
Beth A.
Konicek¶,
Marcelo
A.
Nobrega¶,
Howard
Jacob¶,
David
Walterhouse, and
Philip
Iannaccone**
From the Northwestern University Medical School and
Children's Memorial Institute for Education and Research,
Chicago, Illinois 60614 and ¶ Human and Molecular Genetics
Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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.
*
This work was supported in part by Department of Health and
Human Services United States Public Heath Service Grant PO1 ES10549 from the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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