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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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Related in: MedlinePlus

Control of the GLI code by the oncogenic load. (A) Under normal homeostatic conditions a fine-tuned balance of HH signaling as well as of parallel proto-oncogenic (e.g., EGF, FGF, PDGF, etc.) and tumor-suppressive pathways leads to precisely controlled levels of GLIA/GLIR. The balance can be tipped one way or another, thus allowing for the highly controlled ON-OFF switch. For simplicity, feed-forward and feedback regulatory loops are not included. (B) In cancer, the loss of tumor suppressors and the presence of mutant oncogenes lead to the massive deregulation of the GLI code and to a constitutively active ON state (GLIA). Note that given the stable genetic changes resulting from gene mutation, the GLI code is no longer under homeostatic control.
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fig0010: Control of the GLI code by the oncogenic load. (A) Under normal homeostatic conditions a fine-tuned balance of HH signaling as well as of parallel proto-oncogenic (e.g., EGF, FGF, PDGF, etc.) and tumor-suppressive pathways leads to precisely controlled levels of GLIA/GLIR. The balance can be tipped one way or another, thus allowing for the highly controlled ON-OFF switch. For simplicity, feed-forward and feedback regulatory loops are not included. (B) In cancer, the loss of tumor suppressors and the presence of mutant oncogenes lead to the massive deregulation of the GLI code and to a constitutively active ON state (GLIA). Note that given the stable genetic changes resulting from gene mutation, the GLI code is no longer under homeostatic control.

Mentions: However, surprising data revealed that the GLI1 code and activity can also be modulated by non-HH signals [64,65]. Such regulation occurs in normal and in disease contexts and here we highlight key examples (Fig. 2).


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)

Control of the GLI code by the oncogenic load. (A) Under normal homeostatic conditions a fine-tuned balance of HH signaling as well as of parallel proto-oncogenic (e.g., EGF, FGF, PDGF, etc.) and tumor-suppressive pathways leads to precisely controlled levels of GLIA/GLIR. The balance can be tipped one way or another, thus allowing for the highly controlled ON-OFF switch. For simplicity, feed-forward and feedback regulatory loops are not included. (B) In cancer, the loss of tumor suppressors and the presence of mutant oncogenes lead to the massive deregulation of the GLI code and to a constitutively active ON state (GLIA). Note that given the stable genetic changes resulting from gene mutation, the GLI code is no longer under homeostatic control.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

fig0010: Control of the GLI code by the oncogenic load. (A) Under normal homeostatic conditions a fine-tuned balance of HH signaling as well as of parallel proto-oncogenic (e.g., EGF, FGF, PDGF, etc.) and tumor-suppressive pathways leads to precisely controlled levels of GLIA/GLIR. The balance can be tipped one way or another, thus allowing for the highly controlled ON-OFF switch. For simplicity, feed-forward and feedback regulatory loops are not included. (B) In cancer, the loss of tumor suppressors and the presence of mutant oncogenes lead to the massive deregulation of the GLI code and to a constitutively active ON state (GLIA). Note that given the stable genetic changes resulting from gene mutation, the GLI code is no longer under homeostatic control.
Mentions: However, surprising data revealed that the GLI1 code and activity can also be modulated by non-HH signals [64,65]. Such regulation occurs in normal and in disease contexts and here we highlight key examples (Fig. 2).

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