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Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.

Aberger F, Ruiz I Altaba A - Semin. Cell Dev. Biol. (2014)

Bottom Line: Here, the acquisition of GLI(A) levels above a given threshold is predicted to lead to advanced malignant stages.In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF.Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: fritz.aberger@sbg.ac.at.

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Post-translational modifications regulate GLI transcriptional activity. Fine-tuning of GLI activity by phosphorylation/dephosphorylation and acetylation/deacetylation. Left: fully activated GLI transcription factor with multiple phosphorylated serine/threonine residues in the N-terminal region and the DNA binding domain. In addition, de-acetylation promotes DNA binding affinity and transcriptional activity, respectively. Several kinases (MAPK, S6K, aPKC) and deacetylases catalyze the activation of GLI, while phosphatases, PKA and acetyltransferases negatively regulate GLI activity. Note that PKA phosphorylation of the two amino acid residues C-terminal of the DNA binding domain negatively regulates the transcriptional activity of GLI without affecting processing or stability [161]. ncPKA: non-consensus PKA phosphorylation sites involved in GLI activation.
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fig0030: Post-translational modifications regulate GLI transcriptional activity. Fine-tuning of GLI activity by phosphorylation/dephosphorylation and acetylation/deacetylation. Left: fully activated GLI transcription factor with multiple phosphorylated serine/threonine residues in the N-terminal region and the DNA binding domain. In addition, de-acetylation promotes DNA binding affinity and transcriptional activity, respectively. Several kinases (MAPK, S6K, aPKC) and deacetylases catalyze the activation of GLI, while phosphatases, PKA and acetyltransferases negatively regulate GLI activity. Note that PKA phosphorylation of the two amino acid residues C-terminal of the DNA binding domain negatively regulates the transcriptional activity of GLI without affecting processing or stability [161]. ncPKA: non-consensus PKA phosphorylation sites involved in GLI activation.

Mentions: Post-translational modifications of GLI proteins result in drastic modifications of activity. For instance, phosphorylation and acetylation of GLI1/2 at specific amino acid residues have a major impact on the ability of GLI proteins to regulate target genes by modifying their binding to target promoters (see Fig. 6) [156–158].


Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.

Aberger F, Ruiz I Altaba A - Semin. Cell Dev. Biol. (2014)

Post-translational modifications regulate GLI transcriptional activity. Fine-tuning of GLI activity by phosphorylation/dephosphorylation and acetylation/deacetylation. Left: fully activated GLI transcription factor with multiple phosphorylated serine/threonine residues in the N-terminal region and the DNA binding domain. In addition, de-acetylation promotes DNA binding affinity and transcriptional activity, respectively. Several kinases (MAPK, S6K, aPKC) and deacetylases catalyze the activation of GLI, while phosphatases, PKA and acetyltransferases negatively regulate GLI activity. Note that PKA phosphorylation of the two amino acid residues C-terminal of the DNA binding domain negatively regulates the transcriptional activity of GLI without affecting processing or stability [161]. ncPKA: non-consensus PKA phosphorylation sites involved in GLI activation.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151135&req=5

fig0030: Post-translational modifications regulate GLI transcriptional activity. Fine-tuning of GLI activity by phosphorylation/dephosphorylation and acetylation/deacetylation. Left: fully activated GLI transcription factor with multiple phosphorylated serine/threonine residues in the N-terminal region and the DNA binding domain. In addition, de-acetylation promotes DNA binding affinity and transcriptional activity, respectively. Several kinases (MAPK, S6K, aPKC) and deacetylases catalyze the activation of GLI, while phosphatases, PKA and acetyltransferases negatively regulate GLI activity. Note that PKA phosphorylation of the two amino acid residues C-terminal of the DNA binding domain negatively regulates the transcriptional activity of GLI without affecting processing or stability [161]. ncPKA: non-consensus PKA phosphorylation sites involved in GLI activation.
Mentions: Post-translational modifications of GLI proteins result in drastic modifications of activity. For instance, phosphorylation and acetylation of GLI1/2 at specific amino acid residues have a major impact on the ability of GLI proteins to regulate target genes by modifying their binding to target promoters (see Fig. 6) [156–158].

Bottom Line: Here, the acquisition of GLI(A) levels above a given threshold is predicted to lead to advanced malignant stages.In this review we highlight the concepts of the GLI code, the oncogenic load, the context-dependency of GLI action, and different modes of signaling integration such as that of HH and EGF.Targeting the GLI code directly or indirectly promises therapeutic benefits beyond the direct blockade of individual pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: fritz.aberger@sbg.ac.at.

Show MeSH
Related in: MedlinePlus