The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells

• Published in: Oncogene Vol. 23; no. 6; pp. 1263 - 1274
• Main Authors: REGL, Gerhard, KASPER, Maria, SCHNIDAR, Harald, EICHBERGER, Thomas, NEILL, Graham W, IKRAM, Mohammed S, QUINN, Anthony G, PHILPOTT, Mike P, FRISCHAUF, Anna-Maria, ABERGER, Fritz
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 12.02.2004; Nature Publishing Group
• Subjects: Basal cell carcinoma; Base Sequence; Biological and medical sciences; Cancer; Cdc2 protein; Cell activation; Cell cycle; Cell Cycle - physiology; Cell differentiation; Cell Differentiation - physiology; Cell growth; Cell Line; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Contact inhibition; Contact Inhibition - physiology; Dermatology; DNA Primers; Epidermis; Epidermis - cytology; Epidermis - drug effects; Epidermis - physiology; Epithelial cells; Fundamental and applied biological sciences. Psychology; Gene expression; Humans; Insects; Keratinocytes; Keratinocytes - cytology; Keratinocytes - physiology; Kruppel-Like Transcription Factors; Ligands; Medical research; Medical sciences; Molecular and cellular biology; Molecular modelling; Mutation; Nuclear Proteins; Reverse Transcriptase Polymerase Chain Reaction; S phase; Signal transduction; Skin cancer; Transcription factors; Transcription Factors - genetics; Transcription Factors - physiology; Transgenic animals; Tumorigenesis; Tumors of the skin and soft tissue. Premalignant lesions; Zinc Finger Protein Gli2; Zinc finger proteins; Zinc Fingers - genetics; Zinc Fingers - physiology; Human; Skin disease; Basal cell carcinoma; GLI proteins; Malignant tumor; keratinocytes; Carcinogenesis; Protein; epidermal differentiation; Structural unit; Cell cycle; hedgehog signalling; Keratinocyte; Inhibition; Differentiation; Transcription factor
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1207240

In stratified epidermis, activation of the Hh/Gli signal transduction pathway has been implicated in the control of cell proliferation and tumorigenesis. The zinc-finger transcription factor Gli2 has been identified as critical mediator of the Hh signal at the distal end of the pathway, but the molecular mechanisms by which Gli2 regulates cell proliferation or induces epidermal malignancies such as basal cell carcinoma are still unclear. Here, we provide evidence for a role of human GLI2 in antagonizing contact inhibition and epidermal differentiation. We show by gene expression profiling that activation of the GLI2 oncogene in human keratinocytes activates the transcription of a number of genes involved in cell cycle progression such as E2F1, CCND1, CDC2 and CDC45L, while it represses genes associated with epidermal differentiation. Analysis of the proliferative effect of GLI2 revealed that GLI2 is able to induce G1-S phase progression in contact-inhibited keratinocytes. Detailed time-course experiments identified E2F1 as early transcriptional target of GLI2. Further, we show that GLI2 expression in human keratinocytes results in a marked downregulation of epidermal differentiation markers. The data suggest a role for GLI2 in Hh-induced epidermal neoplasia by opposing epithelial cell cycle arrest signals and epidermal differentiation.