Gli2 is targeted for ubiquitination and degradation by β-TrCP ubiquitin ligase

Neehar Bhatia, Saravanan Thiyagarajan, Irina Elcheva, Mohammed Saleem, Andrzej Dlugosz, Hasan Mukhtar, Vladimir Spiegelman

Research output: Contribution to journalArticle

97 Citations (Scopus)

Abstract

The Hedgehog (Hh) signaling pathway plays a crucial role in embryogenesis and has been linked to the development of several human malignancies. The transcription factor Gli2 plays a key role in the transduction of Hh signals by modulating transcription of some Hh target genes, yet the mechanisms that control Gli2 protein expression are largely unknown. Here we report that β-transducin repeat-containing protein (β-TrCP) E3 ubiquitin ligase is required for Gli2 degradation. β-TrCP2 directly binds wild type Gli2 and promotes its ubiquitination. Single amino acid substitution in Gli2 putative binding site inhibits its interaction with β-TrCP2, its ubiquitination, and stabilizes the Gli2 protein. Stable Gli2 mutant is expressed in higher levels and is more potent in the activation of Gli-dependent transcription as compared with wild type Gli2. We also found that GLI2 protein is expressed highly in prostate cancer cell lines and primary tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate. These data identify β-TrCP2 as a pivotal regulator of Gli2 expression and point to an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer.

Original languageEnglish (US)
Pages (from-to)19320-19326
Number of pages7
JournalJournal of Biological Chemistry
Volume281
Issue number28
DOIs
StatePublished - Jul 14 2006

Fingerprint

Ubiquitination
Transcription
Ligases
Ubiquitin
Prostatic Neoplasms
Transducin
Degradation
Ubiquitin-Protein Ligases
Human Development
Amino Acid Substitution
Tumor Cell Line
Embryonic Development
Tumors
Prostate
Signal Transduction
Proteins
Substitution reactions
Transcription Factors
Genes
Chemical activation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Bhatia, Neehar ; Thiyagarajan, Saravanan ; Elcheva, Irina ; Saleem, Mohammed ; Dlugosz, Andrzej ; Mukhtar, Hasan ; Spiegelman, Vladimir. / Gli2 is targeted for ubiquitination and degradation by β-TrCP ubiquitin ligase. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 28. pp. 19320-19326.
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Gli2 is targeted for ubiquitination and degradation by β-TrCP ubiquitin ligase. / Bhatia, Neehar; Thiyagarajan, Saravanan; Elcheva, Irina; Saleem, Mohammed; Dlugosz, Andrzej; Mukhtar, Hasan; Spiegelman, Vladimir.

In: Journal of Biological Chemistry, Vol. 281, No. 28, 14.07.2006, p. 19320-19326.

Research output: Contribution to journalArticle

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