Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation

Rui Zhang, Sherri Y. Huang, Kay Ka Wai Li, Yen Hsing Li, Wei Hsuan Hsu, Guang Jun Zhang, Chun Ju Chang, Jer Yen Yang

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6 Citations (Scopus)

Abstract

Overexpression of the GLI1 gene has frequently been found in various cancer types, particularly in brain tumors, in which aberrant GLI1 induction promotes cancer cell growth. Therefore, identifying the molecular players controlling GLI1 expression is of clinical importance. Previously, we reported that AMPK directly phosphorylated and destabilized GLI1, resulting in the suppression of the Hedgehog signaling pathway. The current study not only demonstrates that AMPK inhibits GLI1 nuclear localization, but further reveals that β-TrCP plays an essential role in AMPK-induced GLI1 degradation. We found that activation of AMPK promotes the interaction between β-TrCP and GLI1, and induces β-TrCP-mediated GLI1-ubiquitination and degradation. Inhibiting AMPK activity results in the dissociation of the β-TrCP and GLI1 interaction, and diminishes β-TrCP-mediated-GLI1 ubiquitination and degradation. On GLI1, substitution of AMPK phosphorylation sites to aspartic acid (GLI13E) results in stronger binding affinity of GLI1 with β-TrCP, accompanied by enhanced GLI1 ubiquitination and later degradation. In contrast, the GLI1 alanine mutant (GLI13A) shows weaker binding with β-TrCP, which is accompanied by reduced β-TrCP-mediated ubiquitination and degradation. Together, these results demonstrate that AMPK regulates GLI1 interaction with β-TrCP by phosphorylating GLI1 and thus both post-translational modifications by AMPK and β-TrCP ultimately impact GLI1 degradation.

Original languageEnglish
Pages (from-to)49869-49881
Number of pages13
JournalOncotarget
Volume8
Issue number30
DOIs
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

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    Zhang, R., Huang, S. Y., Li, K. K. W., Li, Y. H., Hsu, W. H., Zhang, G. J., Chang, C. J., & Yang, J. Y. (2017). Dual degradation signals destruct GLI1: AMPK inhibits GLI1 through β-TrCP-mediated proteasome degradation. Oncotarget, 8(30), 49869-49881. https://doi.org/10.18632/oncotarget.17769