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

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 GLI2DeltaN (previously thought to represent the entire GLI2 protein), revealing the presence of an amino-terminal repressor domain in the full-length protein. GLI2DeltaN 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.

Pubmed ID: 15994174


  • Roessler E
  • Ermilov AN
  • Grange DK
  • Wang A
  • Grachtchouk M
  • Dlugosz AA
  • Muenke M


Human molecular genetics

Publication Data

August 1, 2005

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR45973
  • Agency: NCI NIH HHS, Id: CA87837
  • Agency: NCI NIH HHS, Id: R01 CA087837
  • Agency: NCI NIH HHS, Id: R01 CA087837-07

Mesh Terms

  • Animals
  • Cells, Cultured
  • DNA, Complementary
  • Female
  • Humans
  • Hypopituitarism
  • Kruppel-Like Transcription Factors
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nuclear Proteins
  • Pedigree
  • Polydactyly
  • Protein Structure, Tertiary
  • Repressor Proteins
  • Trans-Activators
  • Transcriptional Activation
  • Zinc Fingers