title: RNA editing of the GLI1 transcription factor modulates the output of Hedgehog signaling.
abstract: The Hedgehog (HH) signaling pathway has important roles in tumorigenesis and in embryonal patterning. The Glioma-associated 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.
authors: Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden. takshi@nirs.go.jp
authors: Takashi
authors: T
authors: Shimokawa
authors: Mohammed Ferdous-Ur
authors: MF
authors: Rahman
authors: Ulrica
authors: U
authors: Tostar
authors: Enikö
authors: E
authors: Sonkoly
authors: Mona
authors: M
authors: Ståhle
authors: Andor
authors: A
authors: Pivarcsi
authors: Ramesh
authors: R
authors: Palaniswamy
authors: Peter G
authors: PG
authors: Zaphiropoulos
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000071676:Zinc Finger Protein GLI1; D000097603:Dyrk Kinases
chemical_list: D000243:Adenosine Deaminase; D053823:Hedgehog Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000097603:Dyrk Kinases; C400551:GLI1 protein, human; C567955:ADARB1 protein, human
keywords: ADAR1; ADAR2; Hedgehog signaling; RNA editing; basal cell carcinoma; cell proliferation; medulloblastoma; post-transcriptional modification