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J. Biol. Chem., Vol. 283, Issue 18, 12426-12437, May 2, 2008

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GLI2-specific Transcriptional Activation of the Bone Morphogenetic Protein/Activin Antagonist Follistatin in Human Epidermal Cells^*

Thomas Eichberger¹, Alexandra Kaser¹, Claudia Pixner, Carmen Schmid, Stefan Klingler, Martina Winklmayr, Cornelia Hauser-Kronberger, Fritz Aberger, and Anna-Maria Frischauf²

From the Department of Molecular Biology, University of Salzburg, Hellbrunnerstrasse 34 and the Department of Pathology, St. Johann's Hospital, Paracelsus Medical University Salzburg, Muellnerhauptstrasse 48, A-5020 Salzburg, Austria

Hedgehog (HH) signaling in the epidermis is primarily mediated by the zinc finger transcription factors GLI1 and GLI2. Exquisite regulation of HH/GLI signaling is crucial for proper specification of the epidermal lineage and development of its derivatives, whereas dysregulation of HH/GLI signaling disrupts tissue homeostasis and causes basal cell carcinoma (BCC). Similarly, bone morphogenetic proteins (BMPs) and activins have been described as key signaling factors in the complex regulation of epidermal fate decisions, although their precise interplay with HH/GLI is largely elusive. Here we show that, in human epidermal cells, expression of the activin/BMP antagonist follistatin (FST) is predominantly up-regulated by the HH effector GLI2. Consistently, we found strong FST expression in the outer root sheath of human hair follicles and BCC. Detailed promoter analysis showed that two sequences with homology to the GLI consensus binding site are required for GLI2-mediated activation. Interestingly, activation of the FST promoter is highly GLI2-specific, because neither GLI1 nor GLI3 can significantly increase FST transcription. GLI2 specificity requires the presence of a 518-bp fragment in the proximal FST promoter region. On the protein level, sequences C-terminal to the zinc finger are responsible for GLI2-specific activation of FST transcription, pointing to the existence of GLI-interacting cofactors that modulate GLI target specificity. Our results reveal a key role of GLI2 in activation of the activin/BMP antagonist FST in response to HH signaling and provide new evidence for a regulatory interaction between HH and activin/BMP signaling in hair follicle development and BCC.

Received for publication, August 24, 2007 , and in revised form, February 14, 2008.

^* This work was supported by the Austrian Genome Project GENAU Ultrasensitive Proteomics and Genomics II (to A. M. F.), FWF Project 16518-B14 (to F. A.), and the University of Salzburg priority program Biosciences and Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3, Tables S1–S3, and additional references.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 43-662-804-45779; Fax: 43-662-804-4183; E-mail: annemarie.frischauf{at}sbg.ac.at.

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