title: Hedgehog/Gli control by ubiquitination/acetylation interplay.
abstract: Hedgehog is a key morphogen regulating development and leading to tumorigenesis, when hyperactivated. Hedgehog signaling is mediated by transcriptional effectors belonging to the Gli family. Ubiquitination-related posttranslational modifications of the Gli transcription factors, leading to proteasome-dependent proteolytic cleavage or massive degradation, represent an important mechanism of regulation of the pathway. Gli ubiquitination is controlled by a number of E3 ligases belonging to the RING/Cullin and HECT families. These E3 ligases are regulated by several members of the Hh pathway itself (e.g., Smo-activated kinases) as well as by proteins belonging to other signaling cascades (i.e., Numb-activated Itch). These proteolytic signals finally suppress Gli function either directly or indirectly (i.e., suppression of HDAC1-mediated Gli deacetylation). The complex of these regulatory circuitries finely tunes Hedgehog signaling providing a tight control of developmental processes, the subversion of which leads to tumorigenesis. To this regard, these ubiquitination processes represent promising targets for novel therapeutic strategies.
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Lucia
authors.initials: L
authors.lastname: Di Marcotullio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Canettieri
authors.forename: Enrico
authors.initials: E
authors.lastname: De Smaele
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
mesh_terms: D000107:Acetylation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D044767:Ubiquitin-Protein Ligases