The Human Glioma-Associated Oncogene Homolog 1 (GLI1) Family of Transcription Factors in Gene Regulation and Diseases

Zhu, Hongguang; Lo, Hui-Wen

doi:10.2174/138920210791233108

Cited by 65 publications

(53 citation statements)

References 66 publications

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“…As expected, the transcripts of several Gli1 target genes, including endogenous GLI1 , PTCH1 , IGFBP6 , CCND1 , BCL2 , and SNAIL1 (32), were lower in MIA PaCa-2 cells stably expressing R597K-mutant Gli1 (MIA/Gli1RK cells) than in MIA PaCa-2 cells expressing wild-type Gli1 (MIA/Gli1WT cells) (Figure 3A and Supplemental Figure 3A). Consistently, results from a transient reporter assay in 293T cells using Gli binding sequence (GliBS) reporter plasmid (31) confirmed that wild-type Gli1 harbored stronger transcriptional activity compared with R597K-mutant Gli1 (Supplemental Figure 3B).…”

Section: Resultssupporting

confidence: 71%

Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation

et al. 2016

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The oncogenic transcription factor Gli1 is a critical effector in the Hedgehog (Hh) pathway which is necessary for the development and progression of pancreatic ductal adenocarcinoma (PDAC). While TGF-β and K-Ras are known regulators of Gli1 gene transcription in this setting, it is not understood how Gli1 functional activity is regulated. Here we report the identification of Gli1 as a substrate for the protein arginine N-methyltransferase PRMT1 in PDAC. We found that PRMT1 methylates Gli1 at R597, promoting its transcriptional activity by enhancing the binding of Gli1 to its target gene promoters. Interruption of Gli1 methylation attenuates oncogenic functions of Gli1 and sensitizes PDAC cells to gemcitabine treatment. In human PDAC specimens, the levels of both total Gli1 and methylated Gli1 were correlated positively with PRMT1 protein levels. Notably, PRMT1 regulated Gli1 independently of the canonical Hh pathway as well as the TGF-β/Kras-mediated non-canonical Hh pathway, thereby signifying a novel regulatory mechanism for Gli1 transcriptional activity. Taken together, our results identifed a new posttranslational modification of Gli1 that underlies its pivotal oncogenic functions in PDAC.

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Section: Resultssupporting

confidence: 71%

Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation

et al. 2016

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“…The following known Gli-binding sites were used in the search parameters: GAGCAGCCA, GACGACCCC, GGCCCCCCA, GACCGCCCC, AACCAACCCC, GTCCTCCCA, GACCAC CCA (10), GAACACCCA, CACCACCCA and GACCACCAA (11). A pairwise BLAST (basic local alignment search tool, bl2seq, http://blast.ncbi.nlm.nih.gov/Blast.cgi) was performed to compare the promoter region with each GBS.…”

Section: Methodsmentioning

confidence: 99%

Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

et al. 2014

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Cellular resistance to platinum anticancer compounds is governed by no less than two molecular processes; DNA repair and cellular accumulation of drug. Gli1 is an upstream regulator of nucleotide excision repair, effecting this process through c-jun. We, therefore, investigated whether Gli1 plays a role in cellular accumulation of cisplatin. Using a Gli1-specific shRNA, we explored the role of Gli1 in the cellular accumulation and efflux of cisplatin, in cisplatin-resistant A2780-CP70 human ovarian cancer cells. When Gli1 is inhibited, cellular uptake of cisplatin was approximately 33% of the level of uptake under control conditions. When Gli1 is inhibited, cellular efflux of cisplatin was completely abrogated, over a 12-h period of observation. We assayed nuclear lysates from these cells, for the ability to bind the DNA sequence that is the Gli-binding site (GBS) in the 5′UTR for each of five known cisplatin transmembrane transporters. Four of these transporters are active in cisplatin uptake; and, one is active in cisplatin efflux. In each case, nuclear lysate from A2780-CP70 cells binds the GBS of the respective cisplatin transport gene. We conclude that Gli1 plays a strong role in total cellular accumulation of cisplatin in these cells; and, that the combined effects on cellular accumulation of drug and on DNA repair may indicate a role for Gli1 in protecting cellular DNA from lethal types of DNA damage.

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“…GLI1 and GLI3 are mediators of the SHH pathway, which has an effect on the early development of the central nervous system (36). In addition, SHH-GLI1 is involved in the self-renewal of cancer stem cells (37).…”

Section: Discussionmentioning

confidence: 99%

Microarray data analysis of neuroblastoma: Expression of SOX2 downregulates the expression of MYCN

Bao

Qin

Cui

et al. 2015

Molecular Medicine Reports

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Abstract. The present study aimed to identify the genes directly or indirectly correlated with the amplification of MYCN in neuroblastoma (NB). Microarray data (GSE53371) were downloaded from Gene Expression Omnibus, and included 10 NB cell lines with MYCN amplification and 10 NB cell lines with normal MYCN copy numbers. Differentially expressed genes (DEGs) were identified using the Linear Models for Microarray Data package, and a false discovery rate of <0.05 and |log 2 FC (fold change)|>1 were selected as cut-off criteria. Hierarchical clustering analysis and Gene Ontology analysis were respectively performed for the DEGs using the Pheatmap package in R language and The Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction network (PPI) was constructed for the DEGs using the Search Tool for the Retrieval of Interacting Genes database. Pathway analysis was performed for the DEGs in the PPI network using the WEB-based GEne SeT AnaLysis Toolkit. The correlation between MYCN and the key gene associated with MYCN was determined using Pearson's correlation coefficient. In total, 137 downregulated and 35 upregulated DEGs were identified. Functional enrichment analysis indicated that KCNMB4 was involved in the regulation of action potential in neuron term, and the FOS, GLI3 and GLI1 genes were involved in the extracellular matrix-receptor interaction pathway. The PPI network and correlation analysis revealed that the expression of SOX2 was directly correlated with the expression of MYCN, and the correlation coefficient of SOX2 and MYCN was -0.83. Therefore, SOX2, KCNMB4, FOS, GLI3 and GLI1 may be involved in the pathogenesis of NB, with the expression of SOX2 downregulating the expression of MYCN.

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The Human Glioma-Associated Oncogene Homolog 1 (GLI1) Family of Transcription Factors in Gene Regulation and Diseases

Cited by 65 publications

References 66 publications

Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation

Oncogenic Functions of Gli1 in Pancreatic Adenocarcinoma Are Supported by Its PRMT1-Mediated Methylation

Gli1 contributes to cellular resistance to cisplatin through altered cellular accumulation of the drug

Microarray data analysis of neuroblastoma: Expression of SOX2 downregulates the expression of MYCN

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