Hedgehog/GLI signaling activates suppressor of cytokine signaling 1 (SOCS1) in epidermal and neural tumor cells

Sandra Laner-Plamberger; Florian Wolff; Alexandra Kaser-Eichberger; Stefan Swierczynski; Cornelia Hauser-Kronberger; Anna-Maria Frischauf; Thomas Eichberger

doi:10.1371/journal.pone.0075317

Hedgehog/GLI signaling activates suppressor of cytokine signaling 1 (SOCS1) in epidermal and neural tumor cells

PLoS One. 2013 Sep 10;8(9):e75317. doi: 10.1371/journal.pone.0075317. eCollection 2013.

Authors

Sandra Laner-Plamberger¹, Florian Wolff, Alexandra Kaser-Eichberger, Stefan Swierczynski, Cornelia Hauser-Kronberger, Anna-Maria Frischauf, Thomas Eichberger

Affiliation

¹ Department of Molecular Biology, University of Salzburg, Salzburg, Austria ; Department of Blood Group Serology and Transfusion Medicine, University Hospital of Salzburg, Paracelsus Medical University, Salzburg, Austria ; Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria.

Abstract

Sustained hedgehog (Hh) signaling mediated by the GLI transcription factors is implicated in many types of cancer. Identification of Hh/GLI target genes modulating the activity of other pathways involved in tumor development promise to open new ways for better understanding of tumor development and maintenance. Here we show that SOCS1 is a direct target of Hh/GLI signaling in human keratinocytes and medulloblastoma cells. SOCS1 is a potent inhibitor of interferon gamma (IFN-y)/STAT1 signaling. IFN-у/STAT1 signaling can induce cell cycle arrest, apoptosis and anti-tumor immunity. The transcription factors GLI1 and GLI2 activate the SOCS1 promoter, which contains five putative GLI binding sites, and GLI2 binding to the promoter was shown by chromatin immunoprecipitation. Consistent with a role of GLI in SOCS1 regulation, STAT1 phosphorylation is reduced in cells with active Hh/GLI signaling and IFN-у/STAT1 target gene activation is decreased. Furthermore, IFN-у signaling is restored by shRNA mediated knock down of SOCS1. Here, we identify SOCS1 as a novel Hh/GLI target gene, indicating a negative role of Hh/GLI pathway in IFN-y/STAT1 signaling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism*
Humans
Interferon-gamma / genetics
Interferon-gamma / metabolism
Keratinocytes / metabolism*
Keratinocytes / pathology
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Medulloblastoma / genetics
Medulloblastoma / metabolism*
Medulloblastoma / pathology
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phosphorylation / genetics
Response Elements / genetics
Signal Transduction*
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins / genetics
Suppressor of Cytokine Signaling Proteins / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Zinc Finger Protein GLI1
Zinc Finger Protein Gli2

Substances

GLI1 protein, human
GLI2 protein, human
Hedgehog Proteins
IFNG protein, human
Kruppel-Like Transcription Factors
Neoplasm Proteins
Nuclear Proteins
SOCS1 protein, human
Suppressor of Cytokine Signaling 1 Protein
Suppressor of Cytokine Signaling Proteins
Transcription Factors
Zinc Finger Protein GLI1
Zinc Finger Protein Gli2
Interferon-gamma

Grants and funding

This work was supported by the Austrian Genome Project GEN-AU and the University of Salzburg priority program “Biosciences and Health”. FW was supported by the “ICA” doctoral program funded by the Austrian Science Fund. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.