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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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Model for the GLI code and its morphogenetic activity leading to the creation of context-dependent diversity. A gradient of HH ligands is interpreted, canonically, by a combinatorial and context-specific distribution of repressor and activator activities of the three GLI proteins, the GLI code. Note that GLI1 and GLI2 have strong activating action and GLI3 is a strong repressor in many contexts. Combinatorial GLI activities are then modified by positive or negative modifiers leading to differential regulation of target genes, which may either respond to create graded levels of expression of specific genes or induce specific genes in given thresholds. The output of these genetic changes is then the creation of spatially and/or temporally distinct outputs and behaviors.
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fig0005: Model for the GLI code and its morphogenetic activity leading to the creation of context-dependent diversity. A gradient of HH ligands is interpreted, canonically, by a combinatorial and context-specific distribution of repressor and activator activities of the three GLI proteins, the GLI code. Note that GLI1 and GLI2 have strong activating action and GLI3 is a strong repressor in many contexts. Combinatorial GLI activities are then modified by positive or negative modifiers leading to differential regulation of target genes, which may either respond to create graded levels of expression of specific genes or induce specific genes in given thresholds. The output of these genetic changes is then the creation of spatially and/or temporally distinct outputs and behaviors.

Mentions: The GLI code model [21,22] considers the total GLI function as a balance of positive activator (GLIA) and negative repressive (GLIR) activities with GLI1 being mostly a positive transcription factor and GLI3 mostly a transcriptional repressor. The GLIA:GLIR ratio is thus critical, being highly regulated, species- and context-specific, and highly dynamic (Fig. 1).


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)

Model for the GLI code and its morphogenetic activity leading to the creation of context-dependent diversity. A gradient of HH ligands is interpreted, canonically, by a combinatorial and context-specific distribution of repressor and activator activities of the three GLI proteins, the GLI code. Note that GLI1 and GLI2 have strong activating action and GLI3 is a strong repressor in many contexts. Combinatorial GLI activities are then modified by positive or negative modifiers leading to differential regulation of target genes, which may either respond to create graded levels of expression of specific genes or induce specific genes in given thresholds. The output of these genetic changes is then the creation of spatially and/or temporally distinct outputs and behaviors.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0005: Model for the GLI code and its morphogenetic activity leading to the creation of context-dependent diversity. A gradient of HH ligands is interpreted, canonically, by a combinatorial and context-specific distribution of repressor and activator activities of the three GLI proteins, the GLI code. Note that GLI1 and GLI2 have strong activating action and GLI3 is a strong repressor in many contexts. Combinatorial GLI activities are then modified by positive or negative modifiers leading to differential regulation of target genes, which may either respond to create graded levels of expression of specific genes or induce specific genes in given thresholds. The output of these genetic changes is then the creation of spatially and/or temporally distinct outputs and behaviors.
Mentions: The GLI code model [21,22] considers the total GLI function as a balance of positive activator (GLIA) and negative repressive (GLIR) activities with GLI1 being mostly a positive transcription factor and GLI3 mostly a transcriptional repressor. The GLIA:GLIR ratio is thus critical, being highly regulated, species- and context-specific, and highly dynamic (Fig. 1).

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