Gli Proteins in Development and Disease

Hui, Chi‐chung; Angers, Stéphane

doi:10.1146/annurev-cellbio-092910-154048

Cited by 633 publications

(697 citation statements)

References 176 publications

(214 reference statements)

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“…Downstream of SMO, the GLI (glioma-associated oncogene family members) transcription factors mediate HH signal transduction in a process referred to as canonical signaling (reviewed extensively by Briscoe and Therond, 2013;Hui and Angers, 2011). In the absence of HH ligand, GLI2 and GLI3 undergo limited proteasomal degradation, resulting in the cleavage and removal of the GLI C-terminal activator domain, which leads to the conversion of GLI3, and to a lesser extent GLI2, into transcriptional repressors (GLI3 R and GLI2 R ) (Fig.…”

Section: The Hh Signaling Pathway In Mammalsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Section: The Hh Signaling Pathway In Mammalsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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“…Activator forms of Gli (Gli A ) directly induce transcription of Hh target genes, including Ptc1 and Gli gene family members. [27][28][29] The activity of Gli1 depends on Gli2, and Gli1 and Gli2 act primarily as transcriptional activators. Gli3 exists in two forms: a non-processed, full-length form that can function as transcriptional activator, and a truncated aminoterminal fragment that acts as transcriptional repressor.…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

“…Gli3 exists in two forms: a non-processed, full-length form that can function as transcriptional activator, and a truncated aminoterminal fragment that acts as transcriptional repressor. [27][28][29] Also, it has been recently described that the activity of Kif7 at the cilium creates a specialized compartment at the top of the cilia where the activity of the Gli proteins is regulated. 30 The bifunctional Gli proteins have roles in embryogenesis and adult homeostasis as their target genes regulate cell proliferation (cyclin and Myc genes), cell death (Bcl-2), differentiation (genes encoding Forkhead family transcription factors) and stem cell renewal (Bmi-1).…”

Section: Cilium: Structure and Signalingmentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…Ptch inactivation frees the cognate receptor Smo (Smoothened) leading to the downstream activation of a transcriptional program mediated by Gli1, Gli2, and Gli3 (Glioma‐associated oncogene homolog 1, 2, and 3) transcription factors (Hui & Angers, 2011). …”

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Gli Proteins in Development and Disease

Cited by 633 publications

References 176 publications

Roles for Hedgehog signaling in adult organ homeostasis and repair

Roles for Hedgehog signaling in adult organ homeostasis and repair

Autophagy and regulation of cilia function and assembly

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

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