PUBLICATION

Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling

Authors
Serifi, I., Besta, S., Karetsou, Z., Giardoglou, P., Beis, D., Niewiadomski, P., Papamarcaki, T.
ID
ZDB-PUB-210708-2
Date
2021
Source
Scientific Reports   11: 13940 (Journal)
Registered Authors
Papamarcaki, Thomais, Serifi, Iliana
Keywords
none
MeSH Terms
  • Hedgehog Proteins/metabolism*
  • Signal Transduction*
  • Embryo, Nonmammalian/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • NIH 3T3 Cells
  • Humans
  • Transcription, Genetic*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • HEK293 Cells
  • Zinc Finger Protein GLI1/genetics*
  • Zinc Finger Protein GLI1/metabolism
  • Mice
  • CRISPR-Cas Systems/genetics
  • Morpholinos/pharmacology
  • Animals
(all 17)
PubMed
34230583 Full text @ Sci. Rep.
Abstract
The Hedgehog (Hh)/Gli signaling pathway controls cell proliferation and differentiation, is critical for the development of nearly every tissue and organ in vertebrates and is also involved in tumorigenesis. In this study, we characterize the oncoprotein SET/I2PP2A as a novel regulator of Hh signaling. Our previous work has shown that the zebrafish homologs of SET are expressed during early development and localized in the ciliated organs. In the present work, we show that CRISPR/Cas9-mediated knockdown of setb gene in zebrafish embryos resulted in cyclopia, a characteristic patterning defect previously reported in Hh mutants. Consistent with these findings, targeting setb gene using CRISPR/Cas9 or a setb morpholino, reduced Gli1-dependent mCherry expression in the Hedgehog reporter zebrafish line Tg(12xGliBS:mCherry-NLS). Likewise, SET loss of function by means of pharmacological inhibition and gene knockdown prevented the increase of Gli1 expression in mammalian cells in vitro. Conversely, overexpression of SET resulted in an increase of the expression of a Gli-dependent luciferase reporter, an effect likely attributable to the relief of the Sufu-mediated inhibition of Gli1. Collectively, our data support the involvement of SET in Gli1-mediated transcription and suggest the oncoprotein SET/I2PP2A as a new modulator of Hedgehog signaling.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WT + CRISPR1-setbstandard conditionsLong-pec
WT + CRISPR1-setbstandard conditionsLong-pec
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + CRISPR1-setbstandard conditionsPrim-5
ia10Tg + MO2-setbstandard conditionsPrim-5
1 - 10 of 20
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ia10TgTransgenic Insertion
    1 - 1 of 1
    Show
    Human Disease / Model
    No data available
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    setbCRISPR1-setbCRISPR
    setbMO2-setbMRPHLNO
    setbMO3-setbMRPHLNO
    1 - 3 of 3
    Show
    Fish
    Fish
    ia10Tg
    ia10Tg + CRISPR1-setb
    ia10Tg + MO2-setb
    ia10Tg + MO3-setb
    WT + CRISPR1-setb
    WT + MO2-setb
    WT + MO3-setb
    1 - 7 of 7
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    mCherryEFGmCherry
    1 - 1 of 1
    Show
    Mapping
    No data available
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    Citation
    Serifi, I., Besta, S., Karetsou, Z., Giardoglou, P., Beis, D., Niewiadomski, P., Papamarcaki, T. (2021) Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling. Scientific Reports. 11:13940.