Another twist to the GLI code

Abstract

The canonical Hedgehog (Hh) signalling pathway is essential for vertebrate development and its uncontrolled activation is a common occurrence in human cancers. Hh signalling converges in the modification of a family of transcription factors, GLI1, GLI2 and GLI3, to orchestrate a cell type and context-specific transcriptional response. Despite binding to very similar responsive elements, the GLI family members can exert diverse and even opposing functions. A recent article by Tolosa et al. (Biochem. J. 477, 3131–3145, 2020) reveals an unexpected layer of complexity, through physical and functional interaction between GLI1 and GLI2. This commentary discusses the biological significance of the findings and incorporates them into an updated ‘GLI code'.

GLI1 Gene Alterations in Neoplasms of the Genitourinary and Gynecologic Tract

“…The glioma-associated oncogene homolog 1 ( GLI1 ) gene on chromosome 12q13 encodes for a zinc-finger transcription factor which is a downstream effector of the Sonic hedgehog (SHH) signaling pathway 1,2. The SHH pathway plays a key role in embryo development and regulates stem cell differentiation, and it was shown to be aberrantly dysregulated in many human cancers.…”

“…T he glioma-associated oncogene homolog 1 (GLI1) gene on chromosome 12q13 encodes for a zinc-finger transcription factor which is a downstream effector of the Sonic hedgehog (SHH) signaling pathway. 1,2 The SHH pathway plays a key role in embryo development and regulates stem cell differentiation, and it was shown to be aberrantly dysregulated in many human cancers. Inactivating mutations in the negative SHH signaling regulator patched-1 membrane receptor (PTCH1) gene or gain of function mutations in the positive regulator smoothened (SMOH) gene activate GLI1 signaling in many tumor types.…”

From mesenchymal niches to engineered in vitro model systems: Exploring and exploiting biomechanical regulation of vertebrate hedgehog signalling

“…RUNX2 can induce commitment of MSCs into osteoblast lineage cells mainly through the activation of the Hh signalling pathway by directly regulating the expression of its key mediators: IHH, Patched1 (PTCH1) and glioma-associated oncogene homolog 1 (GLI1) [ 17 ]. GLI1 can synergise with RUNX2 by up-regulating RUNX2 expression and further enhances its osteoblastogenic activity in MSCs and osteoblasts [ 19 , 20 ].…”