Journal Article

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

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

in Human Molecular Genetics

Volume 14, issue 15, pages 2181-2188
Published in print August 2005 | ISSN: 0964-6906
Published online June 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi222
A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2

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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 GLI2ΔN (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2ΔN 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.

Journal Article.  4820 words.  Illustrated.

Subjects: Genetics and Genomics

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