Hedgehog/GLI signaling activates suppressor of cytokine signaling 1 (SOCS1) in epidermal and neural tumor cells.
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.
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.
Sandra
S
Laner-Plamberger
Florian
F
Wolff
Alexandra
A
Kaser-Eichberger
Stefan
S
Swierczynski
Cornelia
C
Hauser-Kronberger
Anna-Maria
AM
Frischauf
Thomas
T
Eichberger
D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; C573415:IFNG protein, human; D051741:Kruppel-Like Transcription Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D007371:Interferon-gamma