Primers on molecular pathways GLI: more than just Hedgehog?

Abstract

GLI proteins, highly conserved in vertebrates and invertebrates, are critical in modulating embryonic development and adult tissue homeostasis. These proteins are zinc-finger-containing transcription factors that were originally identified by genetic screening of embryonic lethal mutants of Drosophila melanogaster. Alterations in GLI activity can lead to tumor development in tissues of different origin including the pancreas. GLI activity is mainly regulated by the Hedgehog pathway, via a ligand-receptor complex that triggers a signaling cascade that activates GLI transcription factors, which in turn regulate gene expression, an essential step of Hedgehog-mediated cellular effects. Interestingly, recent reports show the ability of other signaling cascades to modulate GLI function in cancer cells including RAS and TGF-beta, two pathways implicated in pancreatic carcinogenesis. Thus, these findings suggest that GLI proteins are not an exclusive downstream target of Hedgehog but rather a common effector of a network of signaling pathways controlling pancreatic carcinogenesis. and IAP.

Fig. 1.

GLI transcription factors. a Schematic representation of the functional domains of GLI proteins. b Model of Hedgehog-dependent activation of the GLI transcription factors. c Hedgehog-independent regulation of GLI proteins. GLIRep = GLI transcriptional repressor; GLIAct = GLI transcriptional activator; SUFU = Suppressor of FUSED; SMO = SMOOTHENED; PTC = PATCHED.