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Rubinstein−Taybi Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
GCPS shows preaxial polydactyly or mixed pre- and postaxial polydactyly, widely spaced eyes, and macrocephaly. Patients with severe GCPS may have seizures, hydrocephalus, and intellectual disability. About 75% of GCPS cases contain alterations in the GLI3 gene.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: Pallister-Hall syndrome is due to dominant mutations in the gene GLI3 (Gli-Kruppel family member 3), encoding a zinc finger transcription factor. A genotype-phenotype correlation exists; GLI3 mutations that cause a truncated functional repressor protein lead to PHS, whereas haploinsufficiency of GLI3 causes Grieg cephalopolysyndactyly syndrome (GCPS). GLI3 is a critical component of the Shh signalling pathway and is gradually expressed along the dorso–ventral axis. GLI3 and GLI2 are critical elements at the intersection of Shh and retinoic acid pathways in the pre-somitic mesoderm, guaranteeing normal somite formation.
Inhibition of TGF-β1 on Gli2 expression was promoted by TNF-α in primary leukemia cells
Published in Journal of Receptors and Signal Transduction, 2022
Zhe Li, Shudan Mao, Ning Zhang
Hh signaling leads to activation of Gli proteins, which transcriptionally regulate various target genes that determines Hh-dependent survival. This cascade finally leads to cell cycle entry to maintain self-renewal of stem cells in various tissues [9,10], inhibiting apoptosis [11], modulating tissue polarity [12], and regulating tissue stem cell differentiation [13]. Gli proteins consist of three components, namely Gli1, Gli2, and Gli3 [14]. Gli2 is thought to function upstream of Gli1, and to be the upstream effector of Hh signaling pathway [15], activating Gli1 expression via direct binding to the promoter region [16]. Gli3 is proposed to inhibit the activating functions of all co-expressed Gli genes [17]. Recent studies have proposed that Gli proteins may be crosstalk mediators of signaling pathways [3]. For instance, it is reported that Hh/Smo signaling pathway can cross talk with TGF-β signaling pathway via Gli proteins.
Targeting the GLI family of transcription factors for the development of anti-cancer drugs
Published in Expert Opinion on Drug Discovery, 2021
Christopher O Dusek, M Kyle Hadden
The glioma-associated oncogene (GLI) proteins are C2H2-Kruppel type transcription factors that contain five zinc finger domains (ZF1 – ZF5) and bind the consensus DNA sequence 5ʹ-GACCACCCA-3ʹ [1]. There are three GLI proteins (GLI1, GLI2, and GLI3) that serve as either activators or repressors of gene expression depending on the particular homolog and cellular context. Traditionally, GLI-mediated transcriptional regulation has been associated with the roles played by the GLI proteins as downstream effectors of the Hedgehog (HH) signaling pathway, also termed canonical HH/GLI signaling. In this context, GLI1 can serve as a transcriptional activator; however, its primary role is as a transcriptional target of the pathway. HH/GLI-mediated transcription and translation of GLI1 drives the expression of additional genes/proteins that play a role in normal or oncogenic cellular proliferation. In canonical HH/GLI signaling, GLI2 and GLI3 can serve as either transcriptional repressors or activators. Non-canonical upregulation and/or activation of GLI1 through HH-independent mechanisms have been recently implicated as an oncogenic driver for multiple forms of cancer. Inhibition of GLI1-mediated transcriptional activation is emerging as a promising chemotherapeutic strategy to treat a wide range of human malignancies and research programs focused on the identification and development of small molecule GLI1 inhibitors are on the rise. In this review, we briefly discuss canonical and non-canonical GLI1 signaling in cancer, describe several mechanisms through which GLI1 is regulated and highlight promising small molecule GLI1 inhibitors.
Preaxial polydactyly of the foot
Published in Acta Orthopaedica, 2018
Elise B Burger, Martijn Baas, Steven E R Hovius, A Jeannette M Hoogeboom, Christianne A van Nieuwenhoven
In the cohort that was tested for genetic mutations, genetic testing was performed in 39 patients and in 15 affected parents of the patients. In 43 cases this resulted in confirmation of a mutation (Table 3). A GLI3 mutation was confirmed in the largest part of the population (n = 27). In patients with only hand and foot malformations, 14 out of 16 confirmed mutations were in GLI3. In patients with anomalies in the different anatomical groups, 13 out of 27 confirmed mutations were in GLI3.