Context-dependent signal integration by the GLI code: the oncogenic load, pathways, modifiers and implications for cancer therapy.
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.
Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: email@example.com.Show MeSH
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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  (Fig. 5B). Fingers 1 and 2 also provide protein–protein interaction sites to form GLI2, GLI3 and ZIC2 complexes .
Affiliation: Department of Molecular Biology, University of Salzburg, Hellbrunner Strasse 34, 5020 Salzburg, Austria. Electronic address: firstname.lastname@example.org.