RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling

Shimokawa, T., Mohammed Ferdous-Ur, Rahman, Tostar, U., Sonkoly, E., Ståhle, M., Pivarcsi, A., Palaniswamy, R., Zaphiropoulos, P. G. (February 2013) RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling. Rna Biology, 10 (2). pp. 321-333. ISSN 15476286 (ISSN)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/23324600
DOI: 10.4161/rna.23343

Abstract

The Hedgehog (HH) signaling pathway has important roles in tumorigenesis and in embryonal patterning. The Gliomaassociated oncogene 1 (GLI1) is a key molecule in HH signaling, acting as a transcriptional effector and, moreover, is considered to be a potential therapeutic target for several types of cancer. To extend our previous focus on the implications of alternative splicing for HH signal transduction, we now report on an additional post-transcriptional mechanism with an impact on GLI1 activity, namely RNA editing. The GLI1 mRNA is highly edited at nucleotide 2179 by adenosine deamination in normal cerebellum, but the extent of this modification is reduced in cell lines from the cerebellar tumor medulloblastoma. Additionally, basal cell carcinoma tumor samples exhibit decreased GLI1 editing compared with normal skin. Interestingly, knocking down of either ADAR1 or ADAR2 reduces RNA editing of GLI1. This adenosine to inosine substitution leads to a change from Arginine to Glycine at position 701 that influences not only GLI1 transcriptional activity, but also GLI1-dependent cellular proliferation. Specifically, the edited GLI1, GLI1-701G, has a higher capacity to activate most of the transcriptional targets tested and is less susceptible to inhibition by the negative regulator of HH signaling suppressor of fused. However, the Dyrk1a kinase, implicated in cellular proliferation, is more effective in increasing the transcriptional activity of the non-edited GLI1. Finally, introduction of GLI1-701G into medulloblastoma cells confers a smaller increase in cellular growth relative to GLI1. In conclusion, our findings indicate that RNA editing of GLI1 is a regulatory mechanism that modulates the output of the HH signaling pathway. Copyright © 2013 Landes Bioscience.

Item Type: Paper
Uncontrolled Keywords: ADAR1 ADAR2 Basal cell carcinoma Cell proliferation Hedgehog signaling Medulloblastoma Post-transcriptional modification RNA editing
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Osten lab
Depositing User: Matt Covey
Date: February 2013
Date Deposited: 29 Mar 2013 18:16
Last Modified: 29 Mar 2013 18:16
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28065

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