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Human Molecular Genetics Advance Access published online on June 30, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi222
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Published by Oxford University Press 2005
Received May 9, 2005
Revised June 8, 2005
Accepted June 16, 2005

Article

A previously unidentified amino terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2

Erich Roessler 1, Alexandre N. Ermilov 2, Dorothy Katherine Grange 3, Aiqin Wang 2, Marina Grachtchouk 2, Andrzej A. Dlugosz 2, and Maximilian Muenke 4*

1 Medical Genetics Branch, NHGRI, NIH
2 Department of Dermatology and Comprehensive Cancer Center, University of Michigan
3 Department of Pediatrics, Genetics and Genomic Medicine, Washington University
4 Chief, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive - MSC 3717, Building 35, Room 1B-203, Bethesda, MD 20892-3717

* To whom correspondence should be addressed.
Maximilian Muenke, E-mail: mmuenke{at}nhgri.nih.gov


  Abstract

Zinc finger-containing Gli proteins mediate responsiveness to Hedgehog (Hh) signaling, with Gli2 acting as the major transcriptional activator in this pathway in mice. The discovery of disease-associated mutations points to a critical role for GLI2 in human Hh signaling as well. Here we show that human GLI2 contains previously undescribed 5’ sequence, extending the amino-terminus an additional 328 amino acids. In vitro, transcriptional activity of full-length GLI2 is up to 30 times lower than that of GLI2{Delta}N (previously thought to represent the entire GLI2 protein), revealing the presence of an amino terminal repressor domain in the full-length protein. GLI2{Delta}N also exhibits potent transcriptional activity in vivo: overexpression in mouse skin leads to the formation of Hh-independent epithelial downgrowths resembling basal cell carcinomas, which in humans are associated with constitutive Hh signaling. The discovery of this additional, functionally-relevant GLI2 sequence led us to re-examine several pathogenic human GLI2 mutants, now containing the entire amino-terminal domain. Mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity, based on the functional domains affected by the mutations. Moreover, deletion of the amino-terminus abrogated dominant-negative activity of mutant GLI2, revealing that this domain is required for transcriptional repressor activity of pathogenic GLI2. Our results establish the presence of an amino-terminal transcriptional repressor domain that plays a critical role in modulating the function of wild-type GLI2, and is essential for dominant-negative activity of a GLI2 mutant associated with human disease.


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