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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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GLI DNA binding and context-dependent target gene regulation. (A) Consensus 9-mer GLI DNA binding motif calculated from experimentally validated GLI binding sites. The motif was generated with a set of 22 experimentally validated GLI binding sites using WebLogo3 [168]. Positions 4C and 6C are essential for DNA binding while basically all other positions allow a certain degree of sequence variation resulting in distinct target gene activation efficiencies. (B) 3D model of the GLI DNA binding domain composed of five zinc fingers and its interaction with the consensus binding sequence. Note that fingers 4 and 5 form extensive base contacts thereby determining binding specificity (source: Protein Databank ID 2GLI; [119]). (C) Non-exhaustive models of context-dependent target gene activation. Here, GLI activator (GLIA) and GLI repressor forms (GLIR) binding the same target sequences refer to the GLI code. (i) Classical target gene activation model with GLIA binding to the promoters of canonical targets such as PTCH1 or HHIP. (ii) Context-dependent interactions of GLIA with co-activators (CoA) or (iii) of GLIR with co-repressors (CoR) modifies the GLI code and expression of HH-GLI targets. (iv) Context-dependent combinatorial binding of GLIA and cooperating transcription factors (TF) (e.g., JUN, SOX2) to common target promoters can also result in synergistic modulation of gene expression.
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fig0025: GLI DNA binding and context-dependent target gene regulation. (A) Consensus 9-mer GLI DNA binding motif calculated from experimentally validated GLI binding sites. The motif was generated with a set of 22 experimentally validated GLI binding sites using WebLogo3 [168]. Positions 4C and 6C are essential for DNA binding while basically all other positions allow a certain degree of sequence variation resulting in distinct target gene activation efficiencies. (B) 3D model of the GLI DNA binding domain composed of five zinc fingers and its interaction with the consensus binding sequence. Note that fingers 4 and 5 form extensive base contacts thereby determining binding specificity (source: Protein Databank ID 2GLI; [119]). (C) Non-exhaustive models of context-dependent target gene activation. Here, GLI activator (GLIA) and GLI repressor forms (GLIR) binding the same target sequences refer to the GLI code. (i) Classical target gene activation model with GLIA binding to the promoters of canonical targets such as PTCH1 or HHIP. (ii) Context-dependent interactions of GLIA with co-activators (CoA) or (iii) of GLIR with co-repressors (CoR) modifies the GLI code and expression of HH-GLI targets. (iv) Context-dependent combinatorial binding of GLIA and cooperating transcription factors (TF) (e.g., JUN, SOX2) to common target promoters can also result in synergistic modulation of gene expression.

Mentions: GLI proteins regulate target gene promoters by binding the consensus sequence GACCACCCA [115,116]. The two cytosines flanking the central adenine in the consensus sequence are essential for binding, while the other positions allow a certain degree of variation (Fig. 5A) [117,118]. Sequence-specific DNA binding to the cis-regulatory region of a GLI target gene mainly involves zinc fingers 4 and 5 which make extensive base contacts within the 9-mer binding sequence, while fingers 2–3 mainly establish a few contacts with the phosphate backbone. Extensive protein–protein contacts between fingers 1 and 2 apparently contribute to the overall stability of the DNA binding domain [119] (Fig. 5B). Fingers 1 and 2 also provide protein–protein interaction sites to form GLI2, GLI3 and ZIC2 complexes [34].


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)

GLI DNA binding and context-dependent target gene regulation. (A) Consensus 9-mer GLI DNA binding motif calculated from experimentally validated GLI binding sites. The motif was generated with a set of 22 experimentally validated GLI binding sites using WebLogo3 [168]. Positions 4C and 6C are essential for DNA binding while basically all other positions allow a certain degree of sequence variation resulting in distinct target gene activation efficiencies. (B) 3D model of the GLI DNA binding domain composed of five zinc fingers and its interaction with the consensus binding sequence. Note that fingers 4 and 5 form extensive base contacts thereby determining binding specificity (source: Protein Databank ID 2GLI; [119]). (C) Non-exhaustive models of context-dependent target gene activation. Here, GLI activator (GLIA) and GLI repressor forms (GLIR) binding the same target sequences refer to the GLI code. (i) Classical target gene activation model with GLIA binding to the promoters of canonical targets such as PTCH1 or HHIP. (ii) Context-dependent interactions of GLIA with co-activators (CoA) or (iii) of GLIR with co-repressors (CoR) modifies the GLI code and expression of HH-GLI targets. (iv) Context-dependent combinatorial binding of GLIA and cooperating transcription factors (TF) (e.g., JUN, SOX2) to common target promoters can also result in synergistic modulation of gene expression.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0025: GLI DNA binding and context-dependent target gene regulation. (A) Consensus 9-mer GLI DNA binding motif calculated from experimentally validated GLI binding sites. The motif was generated with a set of 22 experimentally validated GLI binding sites using WebLogo3 [168]. Positions 4C and 6C are essential for DNA binding while basically all other positions allow a certain degree of sequence variation resulting in distinct target gene activation efficiencies. (B) 3D model of the GLI DNA binding domain composed of five zinc fingers and its interaction with the consensus binding sequence. Note that fingers 4 and 5 form extensive base contacts thereby determining binding specificity (source: Protein Databank ID 2GLI; [119]). (C) Non-exhaustive models of context-dependent target gene activation. Here, GLI activator (GLIA) and GLI repressor forms (GLIR) binding the same target sequences refer to the GLI code. (i) Classical target gene activation model with GLIA binding to the promoters of canonical targets such as PTCH1 or HHIP. (ii) Context-dependent interactions of GLIA with co-activators (CoA) or (iii) of GLIR with co-repressors (CoR) modifies the GLI code and expression of HH-GLI targets. (iv) Context-dependent combinatorial binding of GLIA and cooperating transcription factors (TF) (e.g., JUN, SOX2) to common target promoters can also result in synergistic modulation of gene expression.
Mentions: GLI proteins regulate target gene promoters by binding the consensus sequence GACCACCCA [115,116]. The two cytosines flanking the central adenine in the consensus sequence are essential for binding, while the other positions allow a certain degree of variation (Fig. 5A) [117,118]. Sequence-specific DNA binding to the cis-regulatory region of a GLI target gene mainly involves zinc fingers 4 and 5 which make extensive base contacts within the 9-mer binding sequence, while fingers 2–3 mainly establish a few contacts with the phosphate backbone. Extensive protein–protein contacts between fingers 1 and 2 apparently contribute to the overall stability of the DNA binding domain [119] (Fig. 5B). Fingers 1 and 2 also provide protein–protein interaction sites to form GLI2, GLI3 and ZIC2 complexes [34].

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