Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.
Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC). However, the downstream events underlying Hh/GLI-induced BCC development are still obscure. Using in vitro model systems to analyse the effect of Hh/GLI-signalling in human keratinocytes, we identified a positive feedback mechanism involving the zinc finger transcription factors GLI1 and GLI2. Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2alpha and GLI2beta. Both isoforms were also shown to be expressed at elevated levels in 21 BCCs compared to normal skin. Detailed time course experiments monitoring the transcriptional response of keratinocytes either to GLI1 or to GLI2 suggest that GLI1 is a direct target of GLI2, while activation of GLI2 by GLI1 is likely to be indirect. Furthermore, expression of either GLI2 or GLI1 led to an increase in DNA-synthesis in confluent human keratinocytes. Taken together, these results suggest an important role of the positive GLI1-GLI2 feedback loop in Hh-mediated epidermal cell proliferation.
Regl
Gerhard
G
Institute of Genetics, University of Salzburg, A-5020 Salzburg, Austria.
Neill
Graham W
GW
Eichberger
Thomas
T
Kasper
Maria
M
Ikram
Mohammed S
MS
Koller
Josef
J
Hintner
Helmut
H
Quinn
Anthony G
AG
Frischauf
Anna-Maria
AM
Aberger
Fritz
F
D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004789:Enzyme Activation; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors; D008156:Luciferases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D015513:Oncogene Proteins / Q000502:physiology*; D000072079:Patched Receptors; D016133:Polymerase Chain Reaction; D012313:RNA / Q000378:metabolism; D011956:Receptors, Cell Surface; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D016335:Zinc Fingers
D017931:DNA Primers; D004273:DNA, Neoplasm; C082593:GLI2 protein, human; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D049452:Green Fluorescent Proteins; D012313:RNA; D008156:Luciferases; D000469:Alkaline Phosphatase; D001973:Bromodeoxyuridine