Human Molecular Genetics Advance Access originally published online on June 30, 2005
Human Molecular Genetics 2005 14(15):2181-2188; doi:10.1093/hmg/ddi222
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A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2
1Medical Genetics Branch, NHGRI, NIH, Bethesda, MD 20892-3717, USA, 2Department of Dermatology and Comprehensive Cancer Center, University of Michigan, Ypsilanti, MI, USA and 3Department of Pediatrics, Genetics and Genomic Medicine, Washington University, USA
* To whom correspondence should be addressed at: 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, USA. Tel: +1 3015947487 or 3014028167, Fax:+1 3014807876; Email: mmuenke{at}nhgri.nih.gov
Received May 9, 2005; Revised June 8, 2005; Accepted June 16, 2005
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
N (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2N 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. On the basis of the functional domains affected by the mutations, mutant GLI2 proteins exhibited either loss-of-function or dominant-negative activity. 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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