Disease relevance of GLI1

• Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling [1].
• Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC) [2].
• Because dysregulation of hedgehog signalling is a feature of several benign cartilaginous tumours, expression of the hedgehog target genes PTC1 and GLI1 was examined in this study in samples from human synovial chondromatosis [3].
• Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling [4].
• GLI1 is expressed in human basal cell carcinomas and sarcomas [5].

High impact information on GLI1

• In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop [6].
• Here, we show that this syndrome results from mutations in GLIS3, encoding GLI similar 3, a recently identified transcription factor [7].
• Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling [8].
• De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets [8].
• GLI gene and rhabdomyosarcoma [9].

Chemical compound and disease context of GLI1

• The objective of this paper is to investigate the protein distribution of SHH and its receptor PTC, SMO and transcription factor GLI1 in various odontogenic tumors [10].
• In pregnancy, the gut GLI response to glucose was reduced in the overweight gestational diabetics and abolished in the normal women [11].

Biological context of GLI1

• In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells [1].
• In normal sebaceous glands IHH is expressed in differentiated sebocytes and the transcription factor GLI1 is activated in sebocyte progenitors, suggesting a paracrine signaling mechanism [12].
• The zinc finger transcription factors GLI1 and GLI2 are considered mediators of the HH signal in epidermal cells, although their tumorigenic nature and their relative contribution to tumorigenesis are only poorly understood [13].
• Interestingly, the phenotype of K5-Gli2DeltaN2 mice was strikingly similar to that reported after K5 promoter-driven overexpression of GLI1, which lacks an NH(2)-terminal region homologous to the Gli2 repressor domain [14].
• Using the in vivo tadpole assay system, we further show that misexpression of GLI1 induces CNS hyperproliferation that depends on the activation of endogenous Gli1 function [15].

Anatomical context of GLI1

• Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2alpha and GLI2beta [2].
• Correspondingly, expression of GLI1, a transcription factor and transcriptional product of hedgehog signaling, was increased 8-fold in cancer epithelial cell lines; however, PTCH1, also a transcriptional target of hedgehog signaling in many cell types, was not increased [16].
• Using real-time, quantitative PCR, laser capture microdissection, and immunohistochemistry, distinctive patterns of expression of the hedgehog pathway members patched 1 (PTCH1), smoothened, GLI1, GLI2 and the 3 hedgehog ligands were identified for epithelial cells and stromal fibroblasts in benign breast and breast cancer [16].
• Localization of GLI1 in elongating spermatids shifted from the nucleus to the cytoplasm and became associated with microtubules [17].
• In the adult mouse testis, GLI1 expression localized to the nuclei of germ cells, beginning with pachytene cells and persisting through round spermatids [17].

Associations of GLI1 with chemical compounds

• Tryptophan residues at position 5 in each finger provide numerous non-helical inter-finger contacts reminiscent of those observed in GLI1 zinc fingers 1 and 2 [18].
• SHH, PTC, SMO and GLI1 were detected more in the cytoplasm of the epithelial cells than in stromal cells [10].
• The mRNA expression levels of Ptc1, Gli1, and Coup-TfII were simultaneously downregulated during the period in which the mRNA expression levels of Ihh and Dhh were downregulated in the uterus after administration of EE [19].
• We next show that co-expression of Fu with transcription factors Gli1 and Gli2 significantly increases their protein levels and luciferase reporter activities, which are blocked by GA [20].
• METHODS: Gli1 transcript levels were measured by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using RNA extracted from formalin-fixed, paraffin-embedded tissues of 68 cases of various skin tumors [21].

Physical interactions of GLI1

• Using band shift and luciferase reporter assays, we now show that GLI2 binds the GLI-binding consensus sequence in the GLI1 promoter [22].
• Twist activates GLI1 reporter expression through E-box +482 but requires binding of USF proteins to E-box +157 [5].
• Detailed promoter analysis and gel shift assays identified three GLI binding sites in the human BCL2 cis-regulatory region [13].
• HAN11 binds mDia1 and controls GLI1 transcriptional activity [23].
• Furthermore, when produced in vitro, the GLI3 protein bound specifically to genomic DNA fragments containing GLI-binding sites [24].

Regulatory relationships of GLI1

• GLI2 is expressed in normal human epidermis and BCC and induces GLI1 expression by binding to its promoter [22].
• Apparently FU did not have any effect on SUFU induced inhibition of GLI [25].
• While exogenous GLI1 increased the luciferase activity, exogenous beta-catenin also enhanced the activity under overexpression of GLI1 [26].
• Additionally, deletion mapping of PTCH1 has revealed that the domains encompassed by amino acids 180-786 and 1058-1210 are of highest significance in inhibiting GLI1 gene activation [27].
• This long FU and a much shorter isoform were compared for the ability to regulate GLI1 and GLI2 [25].

Other interactions of GLI1

• In normal embryonic kidney tissue, GLI1 and/or GLI2 were bound to each target gene [28].
• By contrast, treatment of embryonic kidney explants with cyclopamine decreased GLI1 and/or GLI2 binding, and induced binding of GLI3 [28].
• Moreover, we have found that a C-terminal 19-amino acid deletion in SUFU (delta465) is sufficient to abrogate interaction with GLI1 [29].
• Sonic hedgehog (Shh) binds to its receptor patched (PTCH), leading to the activation and repression of target genes via the GLI family of zinc-finger transcription factors [22].
• The kinetics of FOXE1 induction are similar to the known direct target PTCH, and a 2.5 kb upstream fragment containing five GLI-binding sites activates transcription in a reporter assay [30].

Analytical, diagnostic and therapeutic context of GLI1

• Using expression profiling and quantitative reverse transcriptase PCR, we identified a set of 19 genes whose transcription is synergistically induced by GLI1 and parallel EGF treatment [31].
• SHH, DHH, and GLI1 expression was also analyzed in ten snap-frozen specimens by Western blot [32].
• To investigate HH pathway activity in vivo, GLI1 immunohistochemistry was performed on SCLC tumors [33].
• We used immunofluorescence microscopy to examine the subcellular distribution of HAN11, mDia1 and GLI1 [23].
• Gel shift analysis confirmed the ability of the GLI1 protein to bind these sequences [34].

References