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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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A working framework for the GLI code as a node for signal integration. Multiple signaling inputs from diverse pathways, including but not restricted to HH, EGF, FGF, TGFβ, can converge on GLI regulation, changing the GLI code. Integration can also take place above, through crosstalk (gray arrows). The position of the different components is not related to each other but shown as examples of the types of components involved in the signaling cascades. The GLI code, a transcriptional regulatory node, is then modulated by additional context-dependent inputs (arrow and T bar, such as ZIC proteins) that include a negative feedback loop with p53 [35] and a positive feed-forward regulatory loop with NANOG [133]. The outcome, through differential regulation of target genes, is context-dependent and includes change in stemness, survival, proliferation migration and metabolic regulation. This framework can help not only to conceptualize cell behavior resulting from multiple signaling events but also design multi-target therapies to increase efficiency and prevent resistance. Note that each input also has divergent pathways not shown in the scheme.
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fig0015: A working framework for the GLI code as a node for signal integration. Multiple signaling inputs from diverse pathways, including but not restricted to HH, EGF, FGF, TGFβ, can converge on GLI regulation, changing the GLI code. Integration can also take place above, through crosstalk (gray arrows). The position of the different components is not related to each other but shown as examples of the types of components involved in the signaling cascades. The GLI code, a transcriptional regulatory node, is then modulated by additional context-dependent inputs (arrow and T bar, such as ZIC proteins) that include a negative feedback loop with p53 [35] and a positive feed-forward regulatory loop with NANOG [133]. The outcome, through differential regulation of target genes, is context-dependent and includes change in stemness, survival, proliferation migration and metabolic regulation. This framework can help not only to conceptualize cell behavior resulting from multiple signaling events but also design multi-target therapies to increase efficiency and prevent resistance. Note that each input also has divergent pathways not shown in the scheme.

Mentions: Interestingly, initial evidence for non-HH signaling regulating the GLI code came from studies with frog embryos where GLI2 was found to act in the FGF-Brachyury loop in the early mesoderm [87]. In a separate study, the growth of mouse brain neurospheres was found to be dependent on both EGF and Sonic HH (SHH) signaling but only after decreasing their levels [46,47]. This synergism between EGF and SHH [47], together with the regulation of GLI2 by FGF [87], and the regulation of GLI1 by RAS-MEK-AKT [65] opened a new chapter on the regulation of the GLI code, in this case by non-HH signals. These studies predicted the modulation of the GLI code and of GLI1 by peptide growth factors acting upstream of RAS, MEK and AKT such as FGF, EGF, and many other ligands that trigger receptor tyrosine kinases and activate RAS and downstream events. These findings can therefore help to explain why the GLI code and GLI1 in particular, as the final positive feed-forward output, is important in human cancer. The GLI code, and GLI1, act at the tip of a funnel to integrate multiple outputs. Such a funnel idea [22] (Fig. 3) has strong implications for understanding the logic of signaling but also places the GLI code, and GLI1 in particular, in the line of fire for the development of novel therapies against cancer.


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)

A working framework for the GLI code as a node for signal integration. Multiple signaling inputs from diverse pathways, including but not restricted to HH, EGF, FGF, TGFβ, can converge on GLI regulation, changing the GLI code. Integration can also take place above, through crosstalk (gray arrows). The position of the different components is not related to each other but shown as examples of the types of components involved in the signaling cascades. The GLI code, a transcriptional regulatory node, is then modulated by additional context-dependent inputs (arrow and T bar, such as ZIC proteins) that include a negative feedback loop with p53 [35] and a positive feed-forward regulatory loop with NANOG [133]. The outcome, through differential regulation of target genes, is context-dependent and includes change in stemness, survival, proliferation migration and metabolic regulation. This framework can help not only to conceptualize cell behavior resulting from multiple signaling events but also design multi-target therapies to increase efficiency and prevent resistance. Note that each input also has divergent pathways not shown in the scheme.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0015: A working framework for the GLI code as a node for signal integration. Multiple signaling inputs from diverse pathways, including but not restricted to HH, EGF, FGF, TGFβ, can converge on GLI regulation, changing the GLI code. Integration can also take place above, through crosstalk (gray arrows). The position of the different components is not related to each other but shown as examples of the types of components involved in the signaling cascades. The GLI code, a transcriptional regulatory node, is then modulated by additional context-dependent inputs (arrow and T bar, such as ZIC proteins) that include a negative feedback loop with p53 [35] and a positive feed-forward regulatory loop with NANOG [133]. The outcome, through differential regulation of target genes, is context-dependent and includes change in stemness, survival, proliferation migration and metabolic regulation. This framework can help not only to conceptualize cell behavior resulting from multiple signaling events but also design multi-target therapies to increase efficiency and prevent resistance. Note that each input also has divergent pathways not shown in the scheme.
Mentions: Interestingly, initial evidence for non-HH signaling regulating the GLI code came from studies with frog embryos where GLI2 was found to act in the FGF-Brachyury loop in the early mesoderm [87]. In a separate study, the growth of mouse brain neurospheres was found to be dependent on both EGF and Sonic HH (SHH) signaling but only after decreasing their levels [46,47]. This synergism between EGF and SHH [47], together with the regulation of GLI2 by FGF [87], and the regulation of GLI1 by RAS-MEK-AKT [65] opened a new chapter on the regulation of the GLI code, in this case by non-HH signals. These studies predicted the modulation of the GLI code and of GLI1 by peptide growth factors acting upstream of RAS, MEK and AKT such as FGF, EGF, and many other ligands that trigger receptor tyrosine kinases and activate RAS and downstream events. These findings can therefore help to explain why the GLI code and GLI1 in particular, as the final positive feed-forward output, is important in human cancer. The GLI code, and GLI1, act at the tip of a funnel to integrate multiple outputs. Such a funnel idea [22] (Fig. 3) has strong implications for understanding the logic of signaling but also places the GLI code, and GLI1 in particular, in the line of fire for the development of novel therapies against cancer.

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