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      Gli Proteins: Regulation in Development and Cancer

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          Abstract

          Gli proteins are transcriptional effectors of the Hedgehog signaling pathway. They play key roles in the development of many organs and tissues, and are deregulated in birth defects and cancer. We review the molecular mechanisms of Gli protein regulation in mammals, with special emphasis on posttranslational modifications and intracellular transport. We also discuss how Gli proteins interact with co-activators and co-repressors to fine-tune the expression of Hedgehog target genes. Finally, we provide an overview of the regulation of developmental processes and tissue regeneration by Gli proteins and discuss how these proteins are involved in cancer progression, both through canonical regulation via the Hedgehog pathway and through cross-talk with other signaling pathways.

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          Patched1 regulates hedgehog signaling at the primary cilium.

          Rajat Rohatgi, Ljiljana Milenkovic, Matthew P. Scott (2007)
          Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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            HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity.

            Virginie Clement, Pilar Cartón Sánchez, Nicolas de Tribolet … (2007)
            Cancer stem cells are rare tumor cells characterized by their ability to self-renew and to induce tumorigenesis. They are present in gliomas and may be responsible for the lethality of these incurable brain tumors. In the most aggressive and invasive type, glioblastoma multiforme (GBM), an average of about one year spans the period between detection and death [1]. The resistence of gliomas to current therapies may be related to the existence of cancer stem cells [2-6]. We find that human gliomas display a stemness signature and demonstrate that HEDGEHOG (HH)-GLI signaling regulates the expression of stemness genes in and the self-renewal of CD133(+) glioma cancer stem cells. HH-GLI signaling is also required for sustained glioma growth and survival. It displays additive and synergistic effects with temozolomide (TMZ), the current chemotherapeutic agent of choice. TMZ, however, does not block glioma stem cell self-renewal. Finally, interference of HH-GLI signaling with cyclopamine or through lentiviral-mediated silencing demonstrates that the tumorigenicity of human gliomas in mice requires an active pathway. Our results reveal the essential role of HH-GLI signaling in controlling the behavior of human glioma cancer stem cells and offer new therapeutic possibilities.
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              A paracrine requirement for hedgehog signalling in cancer.

              Robert Yauch, Stephen Gould, Suzie Scales … (2008)
              Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 11 February 2019
                Publication date Collection: February 2019
                Volume: 8
                Issue: 2
                Electronic Location Identifier: 147
                Affiliations
                Centre of New Technologies, University of Warsaw, Banacha 2c, 02-097 Warsaw, Poland; s.niedziolka@ 123456cent.uw.edu.pl (S.M.N.); l.markiewicz@ 123456cent.uw.edu.pl (Ł.M.); t.uspienski@ 123456cent.uw.edu.pl (T.U.); b.baran@ 123456cent.uw.edu.pl (B.B.); k.chojnowska@ 123456cent.uw.edu.pl (K.C.)
                Author notes
                [* ]Correspondence: p.niewiadomski@ 123456cent.uw.edu.pl ; Tel.: +48-22-554-3693
                Author information
                https://orcid.org/0000-0001-6254-6162
                Article
                Publisher ID: cells-08-00147
                DOI: 10.3390/cells8020147
                PMC ID: 6406693
                PubMed ID: 30754706
                SO-VID: 72980d2a-c821-4633-9b5a-585936b5d154
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 04 January 2019
                Date accepted : 02 February 2019
                Categories
                Subject: Review

                Keywords: hedgehog signaling,gli proteins,posttranslational modifications,primary cilia,cancer,developmental signaling,morphogen signaling,nuclear import
                Data availability:
                Keywords: hedgehog signaling, gli proteins, posttranslational modifications, primary cilia, cancer, developmental signaling, morphogen signaling, nuclear import

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